Phosphodiesterase inhibitors and nitric oxide donors, compositions and methods of use

ABSTRACT

The invention describes novel compositions containing at least one phosphodiesterase inhibitor, and at least one compound that donate, transfer or release nitric oxide, elevate endogenous levels of endothelium-derived relaxing factor, stimulate endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and/or one or more vasoactive agents. The invention also provides methods for treating or preventing sexual dysfunctions in males and females, for enhancing sexual responses in males and females, and for treating or preventing diseases induced by the increased metabolism of cyclic guanosine 3′,5′-monophosphate (cGMP), such as hypertension, pulmonary hypertension, congestive heart failure, renal failure, myocardial infraction, stable, unstable and variant (Prinzmetal) angina, atherosclerosis, cardiac edema, renal insufficiency, nephrotic edema, hepatic edema, stroke, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, dementia, immunodeficiency, premature labor, dysmenorrhoea, benign prostatic hyperplasis (BPH), bladder outlet obstruction, incontinence, conditions of reduced blood vessel patency, e.g., postpercutaneous transluminal coronary angioplasty (post-PTCA), peripheral vascular disease, allergic rhinitis, glucoma, and diseases characterized by disorders of gut motility, e.g., irritable bowel syndrome (IBS).

RELATED APPLICATIONS

[0001] This application is (i) a divisional of U.S. application Ser. No.10/216,866, filed Aug. 13, 2002, which is a divisional of U.S.application Ser. No. 09/941,691, filed Aug. 30, 2001, issued as U.S.Pat. No. 6,462,044, which is a continuation of U.S. application Ser. No.09/387,727, filed Sep. 1, 1999, issued as U.S. Pat. No. 6,331,543, whichis a continuation-in-part of U.S. application Ser. No. 09/145,142, filedSep. 1, 1998, issued as U.S. Pat. No. 5,958,926 and RE 37,234, which isa continuation-in-part of U.S. application Ser. No. 08/740,764, filedNov. 1, 1996, issued as U.S. Pat. No. 5,874,437; and (ii) acontinuation-in-part of PCT/US97/19870, filed Oct. 31, 1997, whichclaims priority to U.S. application Ser. No. 08/740,764, filed Nov. 1,1996, issued as U.S. Pat. No. 5,874,437.

[0002] This application is also related to U.S. Pat. Nos. 6,133,272,6,172,060, 6,172,068, 6,177,428, 6,197,782, 6,197,778, 6,211,179,6,221,881, 6,232,321 and 6,316,457.

FIELD OF THE INVENTION

[0003] The present invention describes novel nitrosated and/ornitrosylated phosphodiesterase inhibitors, and novel compositionscomprising at least one nitrosated and/or nitrosylated phosphodiesteraseinhibitor, and, optionally, at least one compound that donates,transfers or releases nitric oxide, elevates endogenous levels ofendothelium-derived relaxing factor, stimulates endogenous synthesis ofnitric oxide or is a substrate for nitric oxide synthase, and/or atleast one vasoactive agent. The present invention also provides novelcompositions comprising at least one phosphodiesterase inhibitor, and atleast one compound that donates, transfers or releases nitric oxide,elevates endogenous levels of endothelium-derived relaxing factor,stimulates endogenous synthesis of nitric oxide or is a substrate fornitric oxide synthase, and/or at least one vasoactive agent. The presentinvention also provides methods for treating or preventing sexualdysfunctions in males and females, for enhancing sexual responses inmales and females, and for treating or preventing diseases induced bythe increased metabolism of cyclic guanosine 3′,5′-monophosphate (cGMP),such as hypertension, pulmonary hypertension, congestive heart failure,renal failure, myocardial infraction, stable, unstable and variant(Prinzmetal) angina, atherosclerosis, cardiac edema, renalinsufficiency, nephrotic edema, hepatic edema, stroke, asthma,bronchitis, chronic obstructive pulmonary disease (COPD), cysticfibrosis, dementia, immunodeficiency, premature labor, dysmenorrhoea,benign prostatic hyperplasis (BPH), bladder outlet obstruction,incontinence, conditions of reduced blood vessel patency, e.g.,postpercutaneous transluminal coronary angioplasty (post-PTCA),peripheral vascular disease, allergic rhinitis, and glucoma, anddiseases characterized by disorders of gut motility, such as irritablebowel syndrome (IBS).

BACKGROUND OF THE INVENTION

[0004] Adequate sexual function is a complex interaction of hormonalevents and psychosocial relationships. There are four stages to sexualresponse as described in the International Journal of Gynecology &Obstetrics, 51(3):265-277 (1995). The first stage of sexual response isdesire. The second stage of sexual response is arousal. Both physicaland emotional stimulation may lead to breast and genital vasodilationand clitoral engorgement (vasocongestion). In the female, dilation andengorgement of the blood vessels in the labia and tissue surrounding thevagina produce the “orgasmic platform,” an area at the distal third ofthe vagina where blood becomes sequestered. Localized perivaginalswelling and vaginal lubrication make up the changes in this stage ofsexual response. Subsequently, ballooning of the proximal portion of thevagina and elevation of the uterus occurs. In the male, vasodilation ofthe cavernosal arteries and closure of the venous channels that drainthe penis produce an erection. The third stage of sexual response isorgasm, while the fourth stage is resolution. Interruption or absence ofany of the stages of the sexual response cycle can result in sexualdysfunction. One study found that 35% of males and 42% of femalesreported some form of sexual dysfunction. Read et al, J. Public HealthMed., 19(4):387-391 (1997).

[0005] While there are obvious differences in the sexual responsebetween males and females, one common aspect of the sexual response isthe erectile response. The erectile response in both males and femalesis the result of engorgement of the erectile tissues of the genitaliawith blood which is caused by the relaxation of smooth muscles in thearteries serving the genitalia.

[0006] In both pre-menopausal and menopausal females, sexual dysfunctioncan include, for example, sexual pain disorders, sexual desiredisorders, sexual arousal dysfunction, orgasmic dysfunction,dyspareunia, and vaginismus. Sexual dysfunction can be caused, forexample, by pregnancy, menopause, cancer, pelvic surgery, chronicmedical illness or medications.

[0007] In males, some pharmacological methods of treating sexualdysfunctions are available, however, such methods have not proven to behighly satisfactory or without potentially severe side-effects.Papaverine now widely used to treat impotence, is generally effective incases where the dysfunction is psychogenic or neurogenic and wheresevere atherosclerosis is not involved. Injection of papaverine, asmooth muscle relaxant, or phenoxybenzamine, a non-specific antagonistand hypotensive, into corpus cavernosum has been found to cause anerection sufficient for vaginal penetration, however, these treatmentsare not without the serious and often painful side effect of priapism.Also, in cases where severe atherosclerosis is not a cause of thedysfunction, intracavernosal injection of phentolamine, analpha-adrenergic antagonist, is used. As an alternative or, in somecases, as an adjunct to alpha-adrenergic blockade, prostaglandin E₁(PGE₁) has been administered via intracavernosal injection. A major sideeffect frequently associated with intracorparally delivered PGE₁ ispenile pain and burning.

[0008] The use of phosphodiesterase inhibitors for the treatment andprevention of diseases induced by the increased metabolism of cyclicguanosine 3′,5′-mono-phosphate (cGMP), such as hypertension, pulmonaryhypertension, congestive heart failure, renal failure, myocardialinfraction, stable, unstable and variant (Prinzmetal) angina,atherosclerosis, cardiac edema, renal insufficiency, nephrotic edema,hepatic edema, stroke, asthma, bronchitis, chronic obstructive pulmonarydisease (COPD), cystic fibrosis, dementia, immunodeficiency, prematurelabor, dysmenorrhoea, benign prostatic hyperplasis (BPH), bladder outletobstruction, incontinence, conditions of reduced blood vessel patency,e.g., postpercutaneous transluminal coronary angioplasty (post-PTCA),peripheral vascular disease, allergic rhinitis, and glucoma, anddiseases characterized by disorders of gut motility, such as irritablebowel syndrome (IBS) have been previously described in, for example,U.S. Pat. Nos. 5,849,741 and 5,869,486, WO98/49166 and WO 97/03985, thedisclosures of each of which are incorporated herein by reference intheir entirety.

[0009] There is a need in the art for new and improved treatments ofsexual dysfunctions and other diseases. The present invention isdirected to these, as well as other, important ends.

SUMMARY OF THE INVENTION

[0010] Nitric oxide (NO) has been shown to mediate a number of actionsincluding the bactericidal and tumoricidal actions of macrophages andblood vessel relaxation of endothelial cells. NO and NO donors have alsobeen implicated as mediators of nonvascular smooth muscle relaxation. Asdescribed herein, this effect includes the dilation of the corpuscavernosum smooth muscle, an event involved in the sexual responseprocess in both males and females. However, the effects of modifiedphosphodiesterase inhibitors, which are directly or indirectly linkedwith a nitric oxide adduct, have not been previously investigated.

[0011] In arriving at the present invention it was recognized that therisk of toxicities and adverse effects that are associated with highdoses of phosphodiesterase inhibitors can be avoided by the use ofnitrosated and/or nitrosylated phosphodiesterase inhibitors or by theuse of at least one phosphodiesterase inhibitor in combination with atleast one nitric oxide donor. Such toxicities and adverse effectsinclude hypotension, syncope, as well as priapism. The smooth musclerelaxant properties of phosphodiesterase inhibitors and of compoundsthat donate, release or transfer nitrogen monoxide or elevate levels ofendogenous endothelium-derived relaxing factor (EDRF) or are substratesfor nitric oxide synthase work together to permit the same efficacy withlower doses of the phosphodiesterase inhibitors or work synergisticallyto produce an effect that is greater than the additive effects of thephosphodiesterase inhibitor and the compound that donates, releases ortransfers nitrogen monoxide or elevates levels of endogenous nitricoxide or EDRF or is a substrates for nitric oxide synthase.

[0012] One aspect of the present invention provides novel nitrosatedand/or nitrosylated phosphodiesterase inhibitors. The phosphodiesteraseinhibitors can be nitrosated and/or nitrosylated through one or moresites such as oxygen (hydroxyl condensation), sulfur (sulfhydrylcondensation), carbon and/or nitrogen. The present invention alsoprovides compositions comprising a therapeutically effective amount ofsuch compounds in a pharmaceutically acceptable carrier.

[0013] Another aspect of the present invention provides compositionscomprising a therapeutically effective amount of at least onephosphodiesterase inhibitor (PDE inhibitor), that is optionallysubstituted with at least one NO and/or NO₂ group (i.e., nitrosylatedand/or nitrosated), and at least one compound that donates, transfers orreleases nitrogen monoxide as a charged species, i.e., nitrosonium (NO⁺)or nitroxyl (NO—), or as the neutral species, nitric oxide (NO.), and/orstimulates endogenous production of nitric oxide or EDRF in vivo and/oris a substrate for nitric oxide synthase. The present invention alsoprovides for such compositions in a pharmaceutically acceptable carrier.

[0014] Yet another aspect of the present invention provides compositionscomprising a therapeutically effective amount of at least onephosphodiesterase inhibitor, that is optionally substituted with atleast one NO and/or NO₂ group (i.e., nitrosylated and/or nitrosated), atleast one vasoactive drug, and, optionally, at least one compound thatdonates, transfers or releases nitrogen monoxide as a charged species,i.e., nitrosonium (NO⁺) or nitroxyl (NO—), or as the neutral species,nitric oxide (NO.), and/or stimulates endogenous production of nitricoxide or EDRF in vivo and/or is a substrate for nitric oxide synthase.The invention also provides for such compositions in a pharmaceuticallyacceptable carrier.

[0015] Yet another aspect of the present invention provides methods fortreating and/or preventing sexual dysfunctions and/or enhancing sexualresponses in patients, including males and females, by administering toa patient in need thereof a therapeutically effective amount of at leastone nitrosated and/or nitrosylated phosphodiesterase inhibitor and,optionally, at least one compound that donates, transfers or releasesnitric oxide as a charged species, i.e., nitrosonium (NO⁺) or nitroxyl(NO—), or as the neutral species, nitric oxide (NO.), and/or stimulatesendogenous production of nitric oxide or EDRF in vivo and/or is asubstrate for nitric oxide synthase. The methods can further compriseadministering a therapeutically effective amount of at least onevasoactive agent. Alternatively, the methods for treating and/orpreventing sexual dysfunctions and/or enhancing sexual responses inpatients, including males and females, can comprise administering atherapeutically effective amount of at least one nitrosated and/ornitrosylated phosphodiesterase inhibitor, at least one vasoactive agent,and, optionally, at least one compound that donates, transfers orreleases nitric oxide as a charged species, i.e., nitrosonium (NO⁺) ornitroxyl (NO—), or as the neutral species, nitric oxide (NO.), and/orstimulates endogenous production of nitric oxide or EDRF in vivo and/oris a substrate for nitric oxide synthase. The nitrosated and/ornitrosylated phosphodiesterase inhibitors, nitric oxide donors, and/orvasoactive agents can be administered separately or as components of thesame composition in one or more pharmaceutically acceptable carriers.

[0016] The present invention also provides methods for treating and/orpreventing sexual dysfunctions and/or enhancing sexual responses inpatients, including males and females, by administering to a patient inneed thereof a therapeutically effective amount of at least onephosphodiesterase inhibitor and at least one compound that donates,transfers or releases nitric oxide as a charged species, i.e.,nitrosonium (NO⁺) or nitroxyl (NO—), or as the neutral species, nitricoxide (NO.), and/or stimulates endogenous production of nitric oxide orEDRF in vivo and/or is a substrate for nitric oxide synthase. Themethods can further comprise administering a therapeutically effectiveamount of at least one vasoactive agent. Alternatively, the methods fortreating and/or preventing sexual dysfunctions and/or enhancing sexualresponses in patients, including males and females, can compriseadministering a therapeutically effective amount of at least onephosphodiesterase inhibitor, at least one vasoactive agent, and,optionally, at least one compound that donates, transfers or releasesnitric oxide as a charged species, i.e., nitrosonium (NO⁺) or nitroxyl(NO—), or as the neutral species, nitric oxide (NO.), and/or stimulatesendogenous production of nitric oxide or EDRF in vivo and/or is asubstrate for nitric oxide synthase. The phosphodiesterase inhibitors,the nitric oxide donors, and the vasoactive agents can be administeredseparately or as components of the same composition in one or morepharmaceutically acceptable carriers.

[0017] The present invention also provides methods using the compoundsand compositions described herein to prevent or treat diseases inducedby the increased metabolism of cyclic guanosine 3′,5′-monophosphate(cGMP), such as hypertension, pulmonary hypertension, congestive heartfailure, myocardial infraction, stable, unstable and variant(Prinzmetal) angina, atherosclerosis, cardiac edema, renalinsufficiency, nephrotic edema, hepatic edema, stroke, asthma,bronchitis, chronic obstructive pulmonary disease (COPD), cysticfibrosis, dementia, immunodeficiency, premature labor, dysmenorrhoea,benign prostatic hyperplasis (BPH), bladder outlet obstruction,incontinence, conditions of reduced blood vessel patency, e.g.,postpercutaneous transluminal coronary angioplasty (post-PTCA),peripheral vascular disease, allergic rhinitis, cystic fibrosis, andglucoma, and diseases characterized by disorders of gut motility, e.g.,irritable bowel syndrome (IBS) by administering to a patient in needthereof a therapeutically effective amount of at least one of thecompounds and/or compositions described herein. In these methods, thephosphodiesterase inhibitors that are optionally nitrosated and/ornitrosylated, nitric oxide donors and vasoactive agents can beadministered separately or as components of the same composition in oneor more pharmaceutically acceptable carriers.

[0018] These and other aspects of the present invention are described indetail herein.

BRIEF DESCRIPTION OF THE DRAWINGS

[0019]FIG. 1 shows a synthetic scheme for the preparation of nitritecontaining substituted benzene derivatives.

[0020]FIG. 2 shows a synthetic scheme for the preparation ofnitrosothiol containing substituted benzene derivatives.

[0021]FIG. 3 shows a synthetic scheme for the preparation of nitratecontaining substituted benzene derivatives.

[0022]FIG. 4 shows a synthetic scheme for the preparation of nitritecontaining imidazo[2,1-b]quinazoline derivatives.

[0023]FIG. 5 shows a synthetic scheme for the preparation ofnitrosothiol containing imidazo[2,1-b]quinazoline derivatives.

[0024]FIG. 6 shows a synthetic scheme for the preparation of nitratecontaining imidazo[2,1-b]quinazoline derivatives.

[0025]FIG. 7 shows a synthetic scheme for the preparation of nitritecontaining purine-6-one derivatives.

[0026]FIG. 8 shows a synthetic scheme for the preparation ofnitrosothiol containing purine-6-one derivatives.

[0027]FIG. 9 shows a synthetic scheme for the preparation of nitratecontaining purine-6-one derivatives.

[0028]FIG. 10 shows a synthetic scheme for the preparation of nitritecontaining pyrimidin-4-one derivatives.

[0029]FIG. 11 shows a synthetic scheme for the preparation ofnitrosothiol containing pyrimidin-4-one derivatives.

[0030]FIG. 12 shows a synthetic scheme for the preparation of nitratecontaining pyrimidin-4-one derivatives.

[0031]FIG. 13 shows a synthetic scheme for the preparation of nitritecontaining 2-pyridone derivatives.

[0032]FIG. 14 shows a synthetic scheme for the preparation ofnitrosothiol containing 2-pyridone derivatives.

[0033]FIG. 15 shows a synthetic scheme for the preparation of nitratecontaining 2-pyridone derivatives.

[0034]FIG. 16 shows a synthetic scheme for the preparation of nitritecontaining purine-2,6-dione derivatives.

[0035]FIG. 17 shows a synthetic scheme for the preparation ofnitrosothiol containing purine-2,6-dione derivatives.

[0036]FIG. 18 shows a synthetic scheme for the preparation of nitratecontaining purine-2,6-dione derivatives.

[0037]FIG. 19 shows a synthetic scheme for the preparation of nitritecontaining quinoline derivatives.

[0038]FIG. 20 shows a synthetic scheme for the preparation ofnitrosothiol containing quinoline derivatives.

[0039]FIG. 21 shows a synthetic scheme for the preparation of nitratecontaining quinoline derivatives.

[0040]FIG. 22 shows a synthetic scheme for the preparation of nitritecontaining substituted pyridine derivatives.

[0041]FIG. 23 shows a synthetic scheme for the preparation ofnitrosothiol containing substituted pyridine derivatives.

[0042]FIG. 24 shows a synthetic scheme for the preparation of nitratecontaining substituted pyridine derivatives.

[0043]FIG. 25 shows a synthetic scheme for the preparation of nitritecontaining benzo[c][1,6]naphthyridine derivatives.

[0044]FIG. 26 shows a synthetic scheme for the preparation ofnitrosothiol containing benzo[c][1,6]naphthyridine derivatives.

[0045]FIG. 27 shows a synthetic scheme for the preparation of nitratecontaining benzo [c][1,6]naphthyridine derivatives.

[0046]FIG. 28 shows a synthetic scheme for the preparation of nitritecontaining 2,6-dihydroxyalkylamino-4,8-dipiperidino pyrimido[5,4-d]pyrimidine derivatives.

[0047]FIG. 29 shows a synthetic scheme for the preparation ofnitrosothiol containing 2,6-dihydroxyalkylamino-4,8-dipiperidinopyrimido[5,4-d]pyrimidine derivatives.

[0048]FIG. 30 shows a synthetic scheme for the preparation of nitratecontaining 2,6-dihydroxyalkylamino-4,8-dipiperidinopyrimido[5,4-d]pyrimidine derivatives.

[0049]FIG. 31 shows a synthetic scheme for the preparation of nitritecontaining 1-((3,4-dihydroxyphenyl)methyl)-6,7-isoquinoline derivatives.

[0050]FIG. 32 shows a synthetic scheme for the preparation ofnitrosothiol containing 1-((3,4-dihydroxyphenyl)methyl)-6,7-isoquinolinederivatives.

[0051]FIG. 33 shows a synthetic scheme for the preparation of nitratecontaining 1-((3,4-dihydroxyphenyl)methyl)-6,7-isoquinoline derivatives.

[0052]FIG. 34 shows a synthetic scheme for the preparation of nitritecontaining substituted quinazoline derivatives.

[0053]FIG. 35 shows a synthetic scheme for the preparation ofnitrosothiol containing substituted quinazoline derivatives.

[0054]FIG. 36 shows a synthetic scheme for the preparation of nitratecontaining substituted quinazoline derivatives.

[0055]FIG. 37 shows a synthetic scheme for the preparation of nitratecontaining substituted phenol derivatives.

[0056]FIG. 38 shows a synthetic scheme for the preparation ofnitrosothiol containing substituted phenol derivatives.

[0057]FIG. 39 shows a synthetic scheme for the preparation of nitratecontaining substituted phenol derivatives.

[0058]FIG. 40 shows a synthetic scheme for the preparation of nitratecontaining substituted5,11,11a,4a-tetrahydropiperazino[1,2-b]beta-carboline-1,4-dionederivatives.

[0059]FIG. 41 shows a synthetic scheme for the preparation ofnitrosothiol containing substituted5,11,11a,4a-tetrahydropiperazino[1,2-b]beta-carboline-1,4-dionederivatives.

[0060]FIG. 42 shows a synthetic scheme for the preparation of nitratecontaining substituted5,11,11a,4a-tetrahydropiperazino[1,2-b]beta-carboline-1,4-dionederivatives.

[0061]FIG. 43 shows a synthetic scheme for the preparation of nitritecontaining substituted 2-acyl-1,2,3,4-tetrahydrobeta-carbolinederivatives.

[0062]FIG. 44 shows a synthetic scheme for the preparation ofnitrosothiol containing substituted2-acyl-1,2,3,4-tetrahydrobeta-carboline derivatives.

[0063]FIG. 45 shows a synthetic scheme for the preparation of nitratecontaining substituted 2-acyl-1,2,3,4-tetrahydrobeta-carbolinederivatives.

[0064]FIG. 46 shows a synthetic scheme for the preparation of nitritecontaining substituted 2-pyrazolin-5-one derivatives.

[0065]FIG. 47 shows a synthetic scheme for the preparation ofnitrosothiol containing substituted 2-pyrazolin-5-one derivatives.

[0066]FIG. 48 shows a synthetic scheme for the preparation of nitratecontaining substituted 2-pyrazolin-5-one derivatives.

[0067]FIG. 49 shows a synthetic scheme for the preparation of nitritecontaining substituted phthalazine derivatives.

[0068]FIG. 50 shows a synthetic scheme for the preparation ofnitrosothiol containing substituted phthalazine derivatives.

[0069]FIG. 51 shows a synthetic scheme for the preparation of nitratecontaining substituted phthalazine derivatives.

[0070]FIG. 52 shows a synthetic scheme for the preparation of nitritecontaining substituted 2-aminobenzamide derivatives.

[0071]FIG. 53 shows a synthetic scheme for the preparation ofnitrosothiol containing substituted 2-aminobenzamide derivatives.

[0072]FIG. 54 shows a synthetic scheme for the preparation of nitratecontaining substituted 2-aminobenzamide derivatives.

[0073]FIG. 55 shows a synthetic scheme for the preparation of nitritecontaining substituted imidazoquinazoline derivatives.

[0074]FIG. 56 shows a synthetic scheme for the preparation ofnitrosothiol containing substituted imidazoquinazoline derivatives.

[0075]FIG. 57 shows a synthetic scheme for the preparation of nitratecontaining substituted imidazoquinazoline derivatives.

[0076]FIG. 58 shows the comparative in vivo relaxation effects ofdipyridamole and the compound of Example 1 in phenylephrine-inducedcontacted human corpus cavernosum tissue.

[0077]FIG. 59 shows the percent peak erectile response in vivo,expressed as intercavernosal pressure (ICP) as a percent of the meanarterial blood pressure (% MABP) in the anesthetized rabbit followingthe administration of (i) sildenafil alone (ii) the combination ofsildenafil and S-nitrosoglutathione (SNO-Glu) (iii) S-nitrosoglutathione(SNO-Glu) alone. The ordinate is the percent response of intracavernosalpressure and the abscissa indicates the compounds administered.

[0078]FIG. 60 shows the duration of the erectile response in vivo in theanesthetized rabbit following the administration of (i) sildenafil alone(ii) the combination of sildenafil and S-nitrosoglutathione (SNO-Glu)(iii) S-nitrosoglutathione (SNO-Glu) alone. The ordinate is the durationin minutes and the abscissa indicates the compounds administered.

DETAILED DESCRIPTION OF THE INVENTION

[0079] The following definitions may be used throughout thespecification.

[0080] “Phosphodiesterase inhibitor” or “PDE inhibitor” refers to anycompound that inhibits the enzyme phosphodiesterase. The term refers toselective or non-selective inhibitors of cyclic guanosine3′,5′-monophosphate phosphodiesterases (cGMP-PDE) and cyclic adenosine3′,5′-monophosphate phosphodiesterases (cAMP-PDE).

[0081] “Patient” refers to animals, preferably mammals, more preferablyhumans.

[0082] “Transurethral” or “intraurethral” refers to delivery of a druginto the urethra, such that the drug contacts and passes through thewall of the urethra and enters into the blood stream.

[0083] “Transdermal” refers to the delivery of a drug by passage throughthe skin and into the blood stream.

[0084] “Transmucosal” refers to delivery of a drug by passage of thedrug through the mucosal tissue and into the blood stream.

[0085] “Penetration enhancement” or “permeation enhancement” refers toan increase in the permeability of the skin or mucosal tissue to aselected pharmacologically active agent such that the rate at which thedrug permeates through the skin or mucosal tissue is increased.

[0086] “Carriers” or “vehicles” refers to carrier materials suitable fordrug administration and include any such material known in the art suchas, for example, any liquid, gel, solvent, liquid diluent, solubilizer,or the like, which is non-toxic and which does not interact with anycomponents of the composition in a deleterious manner.

[0087] “Nitric oxide adduct” or “NO adduct” refers to compounds andfunctional groups which, under physiological conditions, can donate,release and/or directly or indirectly transfer any of the three redoxforms of nitrogen monoxide (NO⁺, NO⁻, NO.), such that the biologicalactivity of the nitrogen monoxide species is expressed at the intendedsite of action.

[0088] “Nitric oxide releasing” or “nitric oxide donating” refers tomethods of donating, releasing and/or directly or indirectlytransferring any of the three redox forms of nitrogen monoxide (NO⁺,NO—, NO.), such that the biological activity of the nitrogen monoxidespecies is expressed at the intended site of action.

[0089] “Nitric oxide donor” or “NO donor” refers to compounds thatdonate, release and/or directly or indirectly transfer a nitric oxidespecies, and/or stimulate the endogenous production of nitric oxide orendothelium-derived relaxing factor (EDRF) in vivo and/or elevateendogenous levels of nitric oxide or EDRF in vivo. “NO donor” alsoincludes compounds that are substrates for nitric oxide synthase.

[0090] “Alkyl” refers to a lower alkyl group, a haloalkyl group, analkenyl group, an alkynyl group, a bridged cycloalkyl group, acycloalkyl group or a heterocyclic ring, as defined herein.

[0091] “Lower alkyl” refers to branched or straight chain acyclic alkylgroup comprising one to about ten carbon atoms (preferably one to abouteight carbon atoms, more preferably one to about six carbon atoms).Exemplary lower alkyl groups include methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, neopentyl, iso-amyl,hexyl, octyl, and the like.

[0092] “Haloalkyl” refers to a lower alkyl group, an alkenyl group, analkynyl group, a bridged cycloalkyl group, a cycloalkyl group or aheterocyclic ring, as defined herein, to which is appended one or morehalogens, as defined herein. Exemplary haloalkyl groups includetrifluoromethyl, chloromethyl, 2-bromobutyl, 1-bromo-2-chloro-pentyl,and the like.

[0093] “Alkenyl” refers to a branched or straight chain C₂-C₁₀hydrocarbon (preferably a C₂-C₈ hydrocarbon, more preferably a C₂-C₆hydrocarbon) which can comprise one or more carbon-carbon double bonds.Exemplary alkenyl groups include propylenyl, buten-1-yl, isobutenyl,penten-1-yl, 2,2-methylbuten-1-yl, 3-methylbuten-1-yl, hexan-1-yl,hepten-1-yl, octen-1-yl, and the like.

[0094] “Alkynyl” refers to an unsaturated acyclic C₂-C₁₀ hydrocarbon(preferably a C₂-C₈ hydrocarbon, more preferably a C₂-C₆ hydrocarbon)which can comprise one or more carbon-carbon triple bonds. Exemplaryalkynyl groups include ethynyl, propynyl, butyn-1-yl, butyn-2-yl,pentyl-1-yl, pentyl-2-yl, 3-methylbutyn-1-yl, hexyl-1-yl, hexyl-2-yl,hexyl-3-yl, 3,3-dimethyl-butyn-1-yl, and the like.

[0095] “Bridged cycloalkyl” refers to two or more cycloalkyl groups,heterocyclic groups, or a combination thereof fused via adjacent ornon-adjacent atoms. Bridged cycloalkyl groups can be unsubstituted orsubstituted with one, two or three substituents independently selectedfrom alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo,carboxyl, alkylcarboxylic acid, aryl, amidyl, ester, alkylcarboxylicester, carboxamido, alkylcarboxamido, oxo and nitro. Exemplary bridgedcycloalkyl groups include adamantyl, decahydronapthyl, quinuclidyl,2,6-dioxabicyclo[3.3.0]octane, 7-oxabycyclo[2.2.1]heptyl and the like.

[0096] “Cycloalkyl” refers to an alicyclic group comprising from about 3to about 7 carbon atoms. Cycloalkyl groups can be unsubstituted orsubstituted with one, two or three substituents independently selectedfrom alkyl, alkoxy, amino, alkylamino, dialkylamino, arylamino,diarylamino, alkylarylamino, aryl, amidyl, ester, hydroxy, halo,carboxyl, alkylcarboxylic acid, alkylcarboxylic ester, carboxamido,alkylcarboxamido, oxo and nitro. Exemplary cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0097] “Heterocyclic ring or group” refers to a saturated or unsaturatedcyclic hydrocarbon group having about 2 to about 10 carbon atoms(preferably about 4 to about 6 carbon atoms) where 1 to about 3 carbonatoms are replaced by one or more nitrogen, oxygen and/or sulfur atoms.The heterocyclic ring or group can be fused to an aromatic hydrocarbongroup. Heterocyclic groups can be unsubstituted or substituted with one,two or three substituents independently selected from alkyl, alkoxy,amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino,hydroxy, oxo, halo, carboxyl, alkylcarboxylic acid, alkylcarboxylicester, aryl, amidyl, ester, carboxamido, alkylcarboxamido,arylcarboxamido, and nitro. Exemplary heterocyclic groups includepyrrolyl, pyridinyl, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl,oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl,tetrhydrofuranyl, tetrazolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl,oxazolindinyl 1,3-dioxolanyl, 2-imidazonlinyl, imidazolindinyl,2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl,1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 2-H-pyranyl,4H-pyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl,thiomorpholinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl,1,3,5-trithianyl, benzo(b)thiophenyl, benzimidazolyl, quinolinyl, andthe like.

[0098] “Heterocyclic compounds” refer to mono- and polycyclic compoundscomprising at least one aryl or heterocyclic ring.

[0099] “Aryl” refers to a monocyclic, bicyclic, carbocyclic orheterocyclic ring system comprising one or two aromatic rings. Exemplaryaryl groups include phenyl, pyridyl, napthyl, quinoyl,tetrahydronaphthyl, furanyl, indanyl, indenyl, indoyl, and the like.Aryl groups (including bicylic aryl groups) can be unsubstituted orsubstituted with one, two or three substituents independently selectedfrom alkyl, alkoxy, amino, alkylamino, dialkylamino, arylamino,diarylamino, alkylarylamino, hydroxy, alkylcarboxylic acid,alkylcarboxylic ester, aryl, amidyl, ester, carboxamido,alkylcarboxamido and nitro. Exemplary substituted aryl groups includetetrafluorophenyl, pentafluorophenyl, and the like.

[0100] “Alkylaryl” refers to an alkyl group, as defined herein, to whichis appended an aryl group, as defined herein. Exemplary alkylaryl groupsinclude benzyl, phenylethyl, hydroxybenzyl, fluorobenzyl,fluorophenylethyl, and the like.

[0101] “Arylalkyl” refers to an aryl radical, as defined herein,attached to an alkyl radical, as defined herein.

[0102] “Cycloalkylalkyl” refers to a cycloalkyl radical, as definedherein, attached to an alkyl radical, as defined herein.

[0103] “Heterocyclicalkyl” refers to a heterocyclic ring radical, asdefined herein, attached to an alkyl radical, as defined herein.

[0104] “Arylheterocyclic ring” refers to a bi- or tricyclic ringcomprised of an aryl ring, as defined herein, appended via two adjacentcarbon atoms of the aryl ring to a heterocyclic ring, as defined herein.Exemplary arylheterocyclic rings include dihydroindole,1,2,3,4-tetra-hydroquinoline, and the like.

[0105] “Alkoxy” refers to R₅₀O—, wherein R₅₀ is an alkyl group, asdefined herein. Exemplary alkoxy groups include methoxy, ethoxy,t-butoxy, cyclopentyloxy, and the like.

[0106] “Arylalkoxy or alkoxyaryl” refers to an alkoxy group, as definedherein, to which is appended an aryl group, as defined herein. Exemplaryarylalkoxy groups include benzyloxy, phenylethoxy, chlorophenylethoxy,and the like.

[0107] “Alkoxyalkyl” refers to an alkoxy group, as defined herein,appended to an alkyl group, as defined herein. Exemplary alkoxyalkylgroups include methoxymethyl, methoxyethyl, isopropoxymethyl, and thelike.

[0108] “Alkoxyhaloalkyl refers to an alkoxy group, as defined herein,appended to a haloalkyl group, as defined herein. Exemplaryalkoxyhaloalkyl groups include 4 methoxy-2-chlorobutyl and the like.

[0109] “Cycloalkoxy” refers to R₅₄O—, wherein R₅₄ is a cycloalkyl groupor a bridged cycloalkyl group, as defined herein. Exemplary cycloalkoxygroups include cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, and thelike.

[0110] “Haloalkoxy” refers to a haloalkyl group, as defined herein, towhich is appended an alkoxy group, as defined herein. Exemplaryhaloalkyl groups include 1,1,1-trichloroethoxy, 2-bromobutoxy, and thelike.

[0111] “Hydroxy” refers to —OH.

[0112] “Oxo” refers to ═O.

[0113] “Hydroxyalkyl” refers to a hydroxy group, as defined herein,appended to an alkyl group, as defined herein.

[0114] “Amino” refers to —NH₂.

[0115] “Nitrate” refers to —O—NO₂.

[0116] “Nitrite” refers to —O—NO.

[0117] “Thionitrate” refers to —S—NO₂.

[0118] “Thionitrite” and “nitrosothiol” refer to —S—NO.

[0119] “Nitro” refers to the group —NO₂ and “nitrosated” refers tocompounds that have been substituted therewith.

[0120] “Nitroso” refers to the group —NO and “nitrosylated” refers tocompounds that have been substituted therewith.

[0121] “Nitrile” and “cyano” refer to —CN.

[0122] “Halogen” or “halo” refers to iodine (I), bromine (Br), chlorine(Cl), and/or fluorine (F).

[0123] “Alkylamino” refers to R₅₀NH—, wherein R₅₀ is an alkyl group, asdefined herein. Exemplary alkylamino groups include methylamino,ethylamino, butylamino, cyclohexylamino, and the like.

[0124] “Arylamino” refers to R₅₅NH—, wherein R₅₅ is an aryl group, asdefined herein.

[0125] “Dialkylamino” refers to R₅₂R₅₃N—, wherein R₅₂ and R₅₃ are eachindependently an alkyl group, as defined herein. Exemplary dialkylaminogroups include dimethylamino, diethylamino, methyl propargylamino, andthe like.

[0126] “Diarylamino” refers to R₅₅R₆₀N—, wherein R₅₅ and R₆₀ are eachindependently an aryl group, as defined herein.

[0127] “Alkylarylamino” refers to R₅₂R₅₅N—, wherein R₅₂ is an alkylgroup, as defined herein and R₅₅ is an aryl group, as defined herein.

[0128] “Aminoalkyl” refers to an amino group, an alkylamino group, adialkylamino group, an arylamino group, a diarylamino group, analkylarylamino group or a heterocyclic ring, as defined herein, to whichis appended an alkyl group, as defined herein.

[0129] “Aminoaryl” refers to an amino group, an alkylamino group, adialkylamino group, an arylamino group, a diarylamino group, analkylarylamino group or a heterocyclic ring, as defined herein, to whichis appended an aryl group, as defined herein.

[0130] “Sulfinyl” refers to —S(O)—.

[0131] “Sulfonyl” refers to —S(O)₂—.

[0132] “Sulfonic acid” refers to —S(O)₂OH

[0133] “Alkylsulfonic acid” refers to a sulfonic acid group, as definedherein, appended to an alkyl group, as defined herein.

[0134] “Arylsulfonic acid” refers to an sulfonic acid group, as definedherein, appended to an aryl group, as defined herein

[0135] “Sulfonic ester” refers to —S(O)₂OR₅₈, wherein R₅₈ is an alkylgroup, an aryl group, an alkylaryl group or an aryl heterocyclic ring,as defined herein.

[0136] “Sulfonamido” refers to —S(O)₂—N(R₅₁)(R₅₇), wherein R₅₁ and R₅₇are each independently a hydrogen atom, an alkyl group, an aryl group,an alkylaryl group, or an arylheterocyclic ring, as defined herein, andR₅₁ and R₅₇ when taken together are a heterocyclic ring, a cycloalkylgroup or a bridged cycloalkyl group, as defined herein.

[0137] “Alkylsulfonamido” refers to a sulfonamido group, as definedherein, appended to an alkyl group, as defined herein.

[0138] “Arylsulfonamido” refers to a sulfonamido group, as definedherein, appended to an aryl group, as defined herein.

[0139] “Alkylthio” refers to R₅₀S—, wherein R₅₀ is an alkyl group, asdefined herein.

[0140] “Arylthio” refers to R₅₅S—, wherein R₅₅ is an aryl group, asdefined herein.

[0141] “Alkylsulfinyl” refers to R₅₀—S(O)—, wherein R₅₀ is an alkylgroup, as defined herein.

[0142] “Alkylsulfonyl” refers to R₅₀—S(O)₂—, wherein R₅₀ is an alkylgroup, as defined herein.

[0143] “Arylsulfinyl” refers to R₅₅—S(O)—, wherein R₅₅ is an aryl group,as defined herein.

[0144] “Arylsulfonyl” refers to R₅₅—S(O)₂—, wherein R₅₅ is an arylgroup, as defined herein.

[0145] “Amidyl” refers to R₅₁C(O)N(R₅₇)— wherein R₅₁ and R₅₇ are eachindependently a hydrogen atom, an alkyl group, an aryl group, analkylaryl group, or an arylheterocyclic ring, as defined herein.

[0146] “Ester” refers to R₅₁C(O)O— wherein R₅₁ is a hydrogen atom, analkyl group, an aryl group, an alkylaryl group, or an arylheterocyclicring, as defined herein.

[0147] “Carbamoyl” refers to —O—C(O)N(R₅₁)(R₅₇), wherein R₅₁ and R₅₇ areeach independently a hydrogen atom, an alkyl group, an aryl group, analkylaryl group or an arylheterocyclic ring, as defined herein, and R₅,and R₅₇ when taken together are a heterocyclic ring, a cycloalkyl groupor a bridged cycloalkyl group, as defined herein.

[0148] “Carboxyl” refers to —CO₂H.

[0149] “Carbonyl” refers to —C(O)—.

[0150] “Methanthial” refers to —C(S)—.

[0151] “Carboxylic ester” refers to —C(O)OR₅₈, wherein R₅₈ is an alkylgroup, an aryl group, an alkylaryl group or an aryl heterocyclic ring,as defined herein.

[0152] “Alkylcarboxylic acid” and “alkylcarboxyl” refer to an alkylgroup, as defined herein, appended to a carboxyl group, as definedherein.

[0153] “Alkylcarboxylic ester” refers to an alkyl group, as definedherein, appended to a carboxylic ester group, as defined herein.

[0154] “Arylcarboxylic acid” refers to an aryl group, as defined herein,appended to a carboxyl group, as defined herein.

[0155] “Arylcarboxylic ester” refers to an aryl group, as definedherein, appended to a carboxylic ester group, as defined herein.

[0156] “Carboxamido” refers to —C(O)N(R₅₁)(R₅₇), wherein R₅₁, and R₅₇are each independently a hydrogen atom, an alkyl group, an aryl group,an alkylaryl group or an arylheterocyclic ring, as defined herein, andR₅₁ and R₅₇ when taken together are a heterocyclic ring, a cycloalkylgroup or a bridged cycloalkyl group, as defined herein.

[0157] “Alkylcarboxamido” refers to an alkyl group, as defined herein,appended to a carboxamido group, as defined herein.

[0158] “Arylcarboxamido” refers to an aryl group, as defined herein,appended to a carboxamido group, as defined herein.

[0159] “Urea” refers to —N(R₅₈)—C(O)N(R₅₁)(R₅₇) wherein R₅₁, R₅₇, andR₅₈ are each independently a hydrogen atom, an alkyl group, an arylgroup, an alkylaryl group, or an arylheterocyclic ring, as definedherein, and R₅₁ and R₅₇ when taken together are a heterocyclic ring, acycloalkyl group or a bridged cycloalkyl group, as defined herein.

[0160] “Phosphoryl” refers to —P(R₇₀)(R₇₁)(R₇₂), wherein R₇₀ is a lonepair of electrons, sulfur or oxygen, and R₇₁ and R₇₂ are eachindependently a covalent bond, a hydrogen, a lower alkyl, an alkoxy, analkylamino, a hydroxy or an aryl, as defined herein.

[0161] “Silyl” refers to —Si(R₇₃)(R₇₄), wherein R₇₃ and R₇₄ are eachindependently a covalent bond, a lower alkyl, an alkoxy, an aryl or anarylalkoxy, as defined herein.

[0162] The term “sexual dysfunction” generally includes any sexualdysfunction in a patient, including an animal, preferably a mammal, morepreferably a human. The patient can be male or female. Sexualdysfunctions can include, for example, sexual desire disorders, sexualarousal disorders, orgasmic disorders and sexual pain disorders. Femalesexual dysfunction refers to any female sexual dysfunction including,for example, sexual desire disorders, sexual arousal dysfunctions,orgasmic dysfunctions, sexual pain disorders, dyspareunia, andvaginismus. The female can be pre-menopausal or menopausal. Male sexualdysfunction refers to any male sexual dysfunctions including, forexample, male erectile dysfunction and impotence.

[0163] The present invention is directed to the treatment and/orprevention of sexual dysfunctions in patients, including males andfemales, by administering the compounds and compositions describedherein. The present invention is also directed to improving and/orenhancing sexual responses in patients, including males and females, byadministering the compounds and/or compositions described herein. Thenovel compounds and novel compositions of the present invention aredescribed in more detail herein.

[0164] Phosphodiesterase inhibitors that may be used in the presentinvention include, for example, filaminast, piclamilast, rolipram, Org20241, MCI-154, roflumilast, toborinone, posicar, lixazinone, zaprinast,sildenafil, pyrazolopyrimidinones (such as those disclosed in WO98/49166), motapizone, pimobendan, zardaverine, siguazodan, CI 930, EMD53998, imazodan, saterinone, loprinone hydrochloride,3-pyridinecarbonitrile derivatives, denbufyllene, albifylline,torbafylline, doxofylline, theophylline, pentoxofylline, nanterinone,cilostazol, cilostamide, MS 857, piroximone, milrinone, amrinone,tolafentrine, dipyridamole, papaverine, E4021, thienopyrimidinederivatives (such as those disclosed in WO 98/17668), triflusal,ICOS-351, tetrahydropiperazino[1,2-b]beta-carboline-1,4-dionederivatives (such as those disclosed in U.S. Pat. No. 5,859,006, WO97/03985 and WO 97/03675), carboline derivatives, (such as thosedisclosed in WO 97/43287), 2-pyrazolin-5-one derivatives (such as thosedisclosed in U.S. Pat. No. 5,869,516), fused pyridazine derivatives(such as those disclosed in U.S. Pat. No. 5,849,741), quinazolinederivatives (such as those disclosed in U.S. Pat. No. 5,614,627),anthranilic acid derivatives (such as those disclosed in U.S. Pat. No.5,714,993), imidazoquinazoline derivatives (such as those disclosed inWO 96/26940), and the like. Also included are those phosphodiesteraseinhibitors disclosed in WO 99/21562 and WO 99/30697. The disclosures ofeach of which are incorporated herein by reference in their entirety.

[0165] Sources of information for the above, and other,phosphodiesterase inhibitors include Goodman and Gilman, ThePharmacological Basis of Therapeutics (9th Ed.), McGraw-Hill, Inc.(1995), The Physician's Desk Reference (49th Ed.), Medical Economics(1995), Drug Facts and Comparisons (1993 Ed), Facts and Comparisons(1993), and The Merck Index (12th Ed.), Merck & Co., Inc. (1996), thedisclosures of each of which are incorporated herein by reference intheir entirety.

[0166] In one embodiment, the present invention describes nitrosatedand/or nitrosylated PDE inhibitors of Formula (I):

[0167] wherein,

[0168] R₁ is an alkoxy, a cycloalkoxy, a halogen, or

[0169] R₂ is a hydrogen, an alkoxy, or a haloalkoxy; and

[0170] R₃ is:

[0171] wherein,

[0172] D is

[0173] (i) —NO,

[0174] (ii) —NO₂,

[0175] (iii) CH(R_(d))—O—C(O)—Y-Z-(C(R_(e))(R_(f)))_(p)-T-Q,

[0176] (iv) —C(O)—Y-Z-(G-(C(R_(e))(R_(f)))_(b)-T-Q)_(p);

[0177] (v) —P-Z-(G-(C(R_(e))(R_(f)))_(b)-T-Q)_(p);

[0178] (vi)—P₁—B₁—W—B_(t)-L_(r)-E_(s)-[C(R_(e))(R_(f))]_(w)-E_(c)-[C(R_(e))(R_(f))]_(x)-L_(d)-[C(R_(e))(R_(f))]_(y)-L_(i)-E_(j)-L_(g)-[C(R_(e))(R_(f))]_(z)-T-Qor

[0179] (vii)—P₁—F′_(n)-L_(r)-E_(s)-[C(R_(e))(R_(f))]_(w)-E_(c)-[C(R_(e))(R_(f))]_(x-L)_(d-[C(R) _(e))(R_(f))]_(y)-L_(i)-E_(j)-L_(g)-[C(R_(e))(R_(f))]_(z)T-Q

[0180] wherein,

[0181] R_(d) is a hydrogen, a lower alkyl, a cycloalkyl, an aryl or anarylalkyl;

[0182] Y is oxygen, S(O)_(o), lower alkyl or NR₁;

[0183] o is an integer from 0 to 2;

[0184] R_(i) is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid,an aryl carboxylic acid, an alkylcarboxylic ester, an arylcarboxylicester, an alkylcarboxamido, an arylcarboxamido, an alkylaryl, analkylsulfinyl, an alkylsulfonyl, an arylsulfinyl, an arylsulfonyl, asulfonamido, a carboxamido, a carboxylic ester,—CH₂—C(T-Q)(R_(e))(R_(f)), or —(N₂O₂—)⁻.M⁺, wherein M⁺ in an organic orinorganic cation;

[0185] R_(e) and R_(f) are each independently a hydrogen, an alkyl, acycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, anarylheterocyclic ring, an alkylaryl, a cycloalkylalkyl, aheterocyclicalkyl, an alkoxy, a haloalkoxy, an amino, an alkylamino, adialkylamino, an arylamino, a diarylamino, an alkylarylamino, analkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, an alkylsulfonic acid,an arylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cyano,an aminoalkyl, an aminoaryl, an alkoxy, an aryl, an arylalkyl, analkylaryl, a carboxamido, a alkyl carboxamido, an aryl carboxamido, anamidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, anarylcarboxylic acid, an ester, a carboxylic ester, an alkylcarboxylicester, an arylcarboxylic ester, a haloalkoxy, a sulfonamido, analkylsulfonamido, an arylsulfonamido, a urea, a nitro, -T-Q, or[C(R_(e))(R_(f))]_(k)-T-Q, or R_(e) and R_(f) taken together are acarbonyl, a methanthial, a heterocyclic ring, a cycloalkyl group or abridged cycloalkyl group;

[0186] k is an integer from 1 to 3;

[0187] p is an integer from 1 to 10;

[0188] T is independently a covalent bond, oxygen, S(O)_(o) or NR₁;

[0189] Z is a covalent bond, an alkyl, an aryl, an arylalkyl, analkylaryl, a heteroalkyl, or (C(R_(e))(R_(f)))_(p);

[0190] Q is —NO or —NO₂;

[0191] G is a covalent bond, -T-C(O)—, —C(O)-T- or T;

[0192] b is an integer from 0 to 5;

[0193] P is a carbonyl, a phosphoryl or a silyl;

[0194] l and t are each independently an integer from 1 to 3;

[0195] r, s, c, d, g, i and j are each independently an integer from 0to 3;

[0196] w, x, y and z are each independently an integer from 0 to 10;

[0197] P₁ is a covalent bond or P;

[0198] B at each occurrence is independently an alkyl group, an arylgroup, or [C(R_(e))(R_(f))]_(p);

[0199] E at each occurrence is independently -T-, an alkyl group, anaryl group, or —(CH₂CH₂O)_(q);

[0200] q is an integer of from 1 to 5;

[0201] L at each occurrence is independently —C(O)—, —C(S)—, -T-, aheterocyclic ring, an aryl group, an alkenyl group, an alkynyl group, anarylheterocyclic ring, or —(CH₂CH₂O)_(q);

[0202] W is oxygen, S(O)₀, or NR₁;

[0203] F′ at each occurrence is independently selected from B orcarbonyl;

[0204] n is an integer from 2 to 5;

[0205] with the proviso that when R_(i) is —CH₂—C(T-Q)(R_(e))(R_(f)) or—(N₂O₂)⁻M⁺, or R_(e) or R_(f) are T-Q or [C(R_(e))(R_(f))]_(k)-T-Q, thenthe “-T-Q” subgroup designated in D can be a hydrogen, an alkyl, analkoxy, an alkoxyalkyl, an aminoalkyl, a hydroxy, or an aryl.

[0206] In cases where multiple designations of variables which reside insequence are chosen as a “covalent bond” or the integer chosen is 0, theintent is to denote a single covalent bond connecting one radical toanother. For example, E₀ or [C(R_(e))(R_(f))]₀ would denote a covalentbond, while E₂ denotes (E-E) and [C(R_(e))(R_(f))]₂ denotes—C(R_(e))(R_(f))—C(R_(e))(R_(f))—.

[0207] R₄ is:

[0208] (i) hydrogen;

[0209] (ii) —CH(R_(d))—O—C(O)—Y-Z-(C(R_(e))(R_(f)))_(p)-T-Q;

[0210] (iii) —C(O)-T-(C(R_(e))(R_(f)))_(p)-T-Q;

[0211] (iv) —C(O)-Z-(G-(C(R_(e))(R_(f)))_(p)-T-Q)_(p), or

[0212] (v)—W_(o)-L_(r)-E_(s)-[C(R_(e))(R_(f))]_(w)-E_(c)-[C(R_(e))(R_(f))]_(x)-L_(d)-[C(R_(e))(R_(f))]_(y)-L_(i)-E_(j)-L_(g)-[C(R_(e))(R_(f))]_(z)-T-Q

[0213] wherein r, s, c, d, g, i, j, o, p, w, x, y, z, R_(d), R_(e)R_(f), E, L, G, T, Q, W, Y, and Z are as defined herein;

[0214] R₅ is a lone pair of electrons or—CH(R_(d))—O—C(O)—Y-Z-(C(R_(e))(R_(f)))_(p)-T-Q;

[0215] R₁₁ and R₁₂ are independently selected from hydrogen or R₄;

[0216] wherein R₄, R_(d), R_(e), R_(f), p, T, Q, Y, and Z are as definedherein;

[0217] X is a halogen, and D₁ is D or hydrogen, wherein D is as definedherein; and with the proviso that if the structure does not contain D,then at least one of the variables R₄, R₅, R₁₁ or R₁₂ must contain theelement “-T-Q”;

[0218] Another embodiment of the present invention provides compounds ofFormula (II):

[0219] wherein,

[0220] R₄ is as defined herein; with the proviso that R₄ cannot behydrogen;

[0221] R₈ is a hydrogen, a lower alkyl group or a haloalkyl group;

[0222] R₉ is a hydrogen or a halogen; and

[0223] R₁₀ is:

[0224] (i) hydrogen,

[0225]  wherein R₈ is as defined herein.

[0226] Another embodiment of the present invention provides compounds ofFormula (III):

[0227] wherein,

[0228] E₁ is nitrogen or —CH—;

[0229] G₁ is nitrogen or —C(R₈)—;

[0230] R₂₁ is:

[0231] R₂₂ is R₁₂ or a lower alkyl;

[0232] R₃₃ is a lower alkyl or [C(R_(e))(R_(f))]_(p)-T-Q; and

[0233] p, R_(e), R_(f), R₁₁, R₁₂, T and Q are as defined herein; withthe proviso that at least one of the variables R₁₁, R₁₂, R₂₂ or R₃₃ mustcontain the element “T-Q”.

[0234] Another embodiment of the present invention provides compounds ofFormula (IV):

[0235] wherein,

[0236] G₂ is —CH₂— or sulfur;

[0237] R₄ and R₈ are each as defined herein; and

[0238] R₁₃ is:

[0239] wherein,

[0240] R₆ and R₇ are independently selected from R₄, wherein R₄ is asdefined herein; with the proviso that at least one of the variables R₄,R₆ or R₇ must contain the element “T-Q”.

[0241] Another embodiment of the present invention provides compounds ofFormula (V):

[0242] wherein,

[0243] R₄ is as defined herein; and

[0244] R₁₄ is:

[0245] wherein R₆ is as defined herein; with the proviso that at leastone of the variables R₄, or R₆ must contain the element “T-Q”.

[0246] Another embodiment of the present invention provides compounds ofFormula (VI):

[0247] wherein,

[0248] R₁₅ is a hydrogen, a lower alkyl, R₄, or —(CH₂)₄—C(CH₃)₂—O-DI;wherein R₄ is as defined herein;

[0249] R₁₆ is a lower alkyl; and

[0250] R₁₇ is a hydrogen, a lower alkyl, CH₃—C(O)—CH₂—; CH₃—O—CH₂—, or Dwith the proviso that either R₁₅ or R₁₇ must contain D, wherein D and D₁are as defined herein.

[0251] Another embodiment of the present invention provides compounds ofFormula (VII):

[0252] wherein,

[0253] R₄ and R₈ are as defined herein; and

[0254] R₁₈ is:

[0255] and wherein R₈ is as defined herein; with the proviso that R₄cannot be hydrogen.

[0256] Another embodiment of the present invention provides compounds ofFormula (VIII):

[0257] wherein,

[0258] R₁₉ is:

[0259] and wherein R₄, R₁₁, and R₁₂ are as defined herein; with theproviso that at least one of the variables R₄, R₁₁ or R₁₂ must containthe element “T-Q”.

[0260] Another embodiment of the present invention provides compounds ofFormula (IX):

[0261] wherein,

[0262] R₂₀ is:

[0263] or (iii) -D;

[0264] wherein R₄ is as defined herein; with the proviso that when R₂₀is not D, then R₄ cannot be hydrogen.

[0265] Another embodiment of the present invention provides compounds ofFormula (X):

[0266] wherein,

[0267] a is an integer from 2 to 3 and D and D₁ are as defined herein.

[0268] Another embodiment of the present invention provides compounds ofFormula (XI):

[0269] wherein,

[0270] D₂ is hydrogen, a lower alkyl or D; wherein D is as definedherein; with the proviso that at least one D₂ must be D.

[0271] Another embodiment of the present invention provides compounds ofFormula (XII):

[0272] wherein,

[0273] R₈ is as defined herein;

[0274] J is:

[0275] R₂₄ is hydrogen or K-G-D;

[0276] wherein,

[0277] K is:

[0278] G₃ is (CH), (CH₂), oxygen, sulfur or nitrogen;

[0279] V is carbon or nitrogen;

[0280] A₁, A₂ and A₃ comprise the other subunits of a 5- or 6-memberedmonocyclic aromatic ring and each is independently (i) C—R₂₃ wherein R₂₃at each occurrence is independently D, a hydrogen, a halogen, an alkoxy,a nitrile, an alkyl, an arylalkyl, an alkylaryl, a carboxamido, acarboxyl, a haloalkyl, an alkoxyalkyl, an alkoxyaryl or a nitro; (ii)sulfur; (iii) oxygen; and (iv) B_(a)=B_(b) wherein B_(a) and B_(b) areeach independently nitrogen or C—R₂₃ wherein at each occurrence R₂₃ isas defined herein; and wherein R₂₆, R₂₇, R₂₈, R₂₉, and R₃₀ areindependently a hydrogen, a halogen, a hydroxy, a haloalkyl, an alkoxy,an alkoxyalkyl, an alkoxyaryl, an alkoxyhaloalkyl, a nitrile, a nitro,an alkyl, an alkylaryl, an arylalkyl, a hydroxy alkyl, a carboxamido, ora carboxyl; and wherein d, g, p, E, L, G, T, Y and D are as definedherein; with the proviso that at least one of the variables A₁, A₂, A₃,J or R₂₄ must contain the element “-T-Q” or “D”.

[0281] Another embodiment of the present invention provides compounds ofFormula (XIII):

[0282] wherein,

[0283] R₃₁ is an alkyl, a halogen, a haloalkyl, or a haloalkoxy;

[0284] R₃₂ is D₁ or —C(O)—R₈; and D, D₁ and R₈ are as defined herein.

[0285] Another embodiment of the present invention provides compounds ofFormula (XIV):

[0286] wherein,

[0287] A is CH₂, a carbonyl or a methanethial;

[0288] G₄ is oxygen or sulfur;

[0289] R₃₄ is hydrogen, lower alkyl, alkenyl, alkynyl orL_(r)-E_(s)-[C(R_(e))(R_(f))]_(w)-E_(c)-[C(R_(e))(R_(f))]_(x)-L_(d)[C(R_(e))(R_(f))]_(y)-L_(i)-E_(j)-L_(g)-[C(R_(e))(R_(f))]_(z)-T-Q;

[0290] R₃₅ and R₃₆ are independently a hydrogen, a lower alkyl, anarylalkyl, an alkylaryl, a cycloalkylalkyl, a heterocyclicalkyl, T-Q or[C(R_(e))(R_(f))]_(k)-T-Q;

[0291] R₃₅ and R₃₆ taken together are a carbonyl group, a methanethialgroup, a heterocyclic group or a cycloalkyl group;

[0292] R₃₄ and R₃₅ taken together are [C(R_(g))(R_(h))]_(u) or—C(R_(g))(R_(h))—C(R_(g))═C(R_(g))—[C(R_(g))(R_(h))]_(v) wherein u is aninteger of 3 or 4, v is an integer of 1 or 2 and R_(g) and R_(h) at eachoccurrence is independently a hydrogen, an alkyl, T-Q or[C(R_(e))(R_(f))]_(k)-T-Q;

[0293] R₃₈ is a hydrogen, a halogen or a lower alkyl; and

[0294] R₃₇ is:

[0295] wherein,

[0296] c, d, g, i, j, k, r, s, w, x, y, z, D_(I), E, L, G₃, T, Q, R_(e),R_(f), R₂₆, R₂₇, R₂₈, R₂₉, R₃₀ and R₃₈ are as defined herein; with theproviso that D₁ must be D if R₃₄, R₃₅ R₃₆ or R₃₇ do not contain theelement “T-Q”.

[0297] Another embodiment of the present invention provides compounds ofFormula (XV):

[0298] wherein,

[0299] R₂₅ at each occurrence is a hydrogen, an alkyl, a cycloalkoxy, ahalogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclicring, an alkylaryl, an arylalkoxy, an alkylthio, an arylthio, a cyano,an aminoalkyl, an amino an alkoxy, an aryl, an arylalkyl, a carboxamido,a alkyl carboxamido, an aryl carboxamido, a carboxyl, a carbamoyl, analkylcarboxylic acid, an arylcarboxylic acid, a carboxylic ester, analkylcarboxylic ester, an arylcarboxylic ester, a carboxamido, analkylcarboxamido, an arylcarboxamido, a haloalkoxy, a sulfonamido, aurea, a nitro, orL_(r)-E_(s)-[C(R_(e))(R_(f))]_(w)-E_(c)-[C(R_(e))(R_(f))]_(x)-L_(d)-[C(R_(e))(R_(f))]_(y)-L_(i)-E_(j)-L_(g)-[C(R_(e))(R_(f))]_(z)-T-Q;and wherein c, d, g, i, j, k, r, s, w, x, y, z, G₄, Di, E, L, T, Q,R_(e), R_(f), R₃₇ and R₃₈ are as defined herein; with the proviso thatD₁ must be D if R_(e) or R₂₅ do not contain the element “T-Q”.

[0300] Another embodiment of the present invention provides compounds ofthe Formula (XVI):

[0301] wherein,

[0302] R₄₀ is a hydrogen, a lower alkyl, a haloalkyl, a halogen, analkoxy, an alkenyl, an alkynyl, a carbamoyl, a sulfonamido orL_(r)-E_(s)-[C(R_(e))(R_(f))]_(w)-E_(c)-[C(R_(e))(R_(f))]_(x)-L_(d)-[C(R_(e))(R_(f))]_(y)-L_(i)-E_(j)-L_(g)[C(R_(e))(R_(f))]_(z)-T-Q;and

[0303] wherein c, d, g, i, j, k, r, s, w, x, y, z, E, L, T, Q, R_(e) andR_(f) are as defined herein;

[0304] R₄₁ is a lower alkyl, a hydroxyalkyl, an alkylcarboxylic acid, analkylcarboxylic ester an alkylcarboxamido orL_(r)-E_(s)-[C(R_(e))(R_(f))]_(w)-E_(c)-[C(R_(e))(R_(f))]_(x)-L_(d)-[C(R_(e))(R_(f))]_(y)-L_(i)-E_(j)-L_(g)-[C(R_(e))(R_(f))]_(z)-T-Q;and

[0305] wherein c, d, g, i, j, k, r, s, w, x, y, z, E, L, T, Q, R_(e) andR_(f) are as defined herein;

[0306] R₄₂ is:

[0307] wherein,

[0308] R₄₃ at each occurrence is independently an amino, a cyano, ahalogen, a nitro group, a carboxyl, a carbamoyl, a sulfonic acid, asulfonic ester, a sulfonamido, a heterocyclic ring, a carboxamido, acarboxylic ester, an ester, an amidyl, a phosphoryl orL_(r)-E_(s)-[C(R_(e))(R_(f))]_(w)-E_(c)-[C(R_(e))(R_(f))]_(x)-L_(d)-[C(R_(e))(R_(f))]_(y)-L_(i)-E_(j)-L_(g)-[C(R_(e))(R_(f))]_(z)-T-Q;and

[0309] c, d, g, i, j, k, r, s, w, x, y, z, E, L, T, Q, R_(e), and R_(f)are as defined herein; with the proviso that at least one of R₄₀, R₄₁,or R₄₃ must contain the element “T-Q”.

[0310] Another embodiment of the present invention provides compounds ofthe Formula (XVII):

[0311] wherein R₈, R₂₃, R₂₄, p and J are as defined herein; with theproviso that at least one R₂₄ or J must contain the element “-T-Q” or“-D”.

[0312] Another embodiment of the present invention provides compounds ofthe Formula (XVIII):

[0313] wherein,

[0314] R₄₄ is:

[0315] wherein d, g, p, D, E, L, G₃, G₄, T, R₈, R₂₆, R₂₇, R₂₈, R₂₉, andR₃₀ are as defined herein.

[0316] Another embodiment of the present invention provides compounds ofthe Formula (XIX):

[0317] wherein,

[0318] R₄₆ and R₄₇ are independently selected from lower alkyl,hydroxyalkyl or D, or R₄₆ and R₄₇ taken together are a heterocyclicring, wherein G₄, T, R₈, and k are defined herein; with the proviso thatat least one of the variables R₄₆ or R₄₇ must be D or when the variablestaken together are a heterocyclic ring, the ring must contain NR_(i),wherein R_(i) must contain the element “T-Q”.

[0319] Compounds of the present invention that have one or moreasymmetric carbon atoms may exist as the optically pure enantiomers,pure diastereomers, mixtures of enantiomers, mixtures of diastereomers,racemic mixtures of enantiomers, diastereomeric racemates or mixtures ofdiastereomeric racemates. The present invention includes within itsscope all such isomers and mixtures thereof.

[0320] Another aspect of the present invention provides processes formaking the novel compounds of the invention and to the intermediatesuseful in such processes. The compounds of the present invention may besynthesized following the reaction schemes shown in FIGS. 1-57, in whichR₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆,R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀,R₃₁, R₃₂, R₃₄, R₃₅, R₃₆, R₃₇, R₃₈, R₃₉R₄₀, R₄₁, R₄₂, R₄₃, R₄₄, R₄₅, R₄₆,R₄₇, R_(e), R_(f), a, p, A, A₁, A₂, A₃, D, D₁, D₂, E₁, G₁, G₂, G₃, G₄,J, K, T and X are as defined herein or as depicted in the reactionschemes for formulas I-XIX; P¹ is an oxygen protecting group and P² is asulfur protecting group. The reactions are performed in solventsappropriate to the reagents, and materials used are suitable for thetransformations being effected. One skilled in the art of organicsynthesis will understand that the functionality present in the moleculemust be consistent with the chemical transformation proposed. This will,on occasion, necessitate judgment by the routine as to the order ofsynthetic steps, protecting groups required, and deprotectionconditions. Substituents on the starting materials may be incompatiblewith some of the reaction conditions required in some of the methodsdescribed, but alternative methods and substituents compatible with thereaction conditions will be readily apparent to the skilled practitionerin the art. The use of sulfur and oxygen protecting groups is well knownin the art for protecting thiol and alcohol groups against undesirablereactions during a synthetic procedure and many such protecting groupsare known, as described, for example, by T. H. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, John Wiley & Sons, New York(1991), the disclosure of which is incorporated by reference herein inits entirety.

[0321] Nitroso compounds of structure (I), wherein R₁, R₂, R_(e), R_(f),and p are as defined herein, and a nitrite containing imide isrepresentative of the R₃ group, as defined herein, may be prepared asshown in FIG. 1. The amide group of structure 1 is converted to theimide of structure 2, wherein p, R_(e) and R_(f) are as defined herein,by reaction with an appropriate protected alcohol containing activatedacylating agent, wherein P¹ is as defined herein. Preferred methods forthe formation of imides are reacting the amide with the preformed acidchloride of the protected alcohol containing acid in the presence ofpyridine at low temperature or condensing the amide and protectedalcohol containing symmetrical anhydride in the presence of a catalyst,such as sulfuric acid. Preferred protecting groups for the alcoholmoiety are silyl ethers, such as a trimethylsilyl ether, atert-butyldimethylsilyl ether, or a tert-butyldiphenylsilyl ether.Deprotection of the hydroxyl moiety (fluoride ion is the preferredmethod for removing silyl ether protecting groups) followed by reactionwith a suitable nitrosylating agent, such as thionyl chloride nitrite,thionyl dinitrite, or nitrosonium tetrafluoroborate, in a suitableanhydrous solvent, such as dichloro-methane, THF, DMF, or acetonitrile,with or without an amine base, such as pyridine or triethylamine affordsthe compound of structure IA.

[0322] Nitroso compounds of structure (I), wherein R₁, R₂, R_(e), R_(f),and p are as defined herein, and a nitrosothiol containing imide isrepresentative of the R₃ group, as defined herein, may be prepared asshown in FIG. 2. The amide group of structure 1 is converted to theimide of structure 3, wherein p, R_(e) and R_(f) are as defined herein,by reaction with an appropriate protected thiol containing activatedacylating agent, wherein P² is as defined herein. Preferred methods forthe formation of imides are reacting the amide with the preformed acidchloride of the protected thiol containing acid in the presence ofpyridine at low temperature or condensing the amide and protected thiolcontaining symmetrical anhydride in the presence of a catalyst, such assulfuric acid. Preferred protecting groups for the thiol moiety are as athioester, such as a thioacetate or thiobenzoate, as a disulfide, as athiocarbamate, such as N-methoxymethyl thiocarbamate, or as a thioether,such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether ora 2,4,6-trimethoxybenzyl thioether. Deprotection of the thiol moiety(zinc in dilute aqueous acid, triphenylphosphine in water and sodiumborohydride are preferred methods for reducing disulfide groups whileaqueous base is typically used to hydrolyze thioesters andN-methoxymethyl thiocarbamates and mercuric trifluoroacetate, silvernitrate, or strong acids, such as trifluoroacetic or hydrochloric acid,and heat are used to remove a paramethoxy-benzyl thioether, atetrahydropyranyl thioether, or a 2,4,6-trimethoxybenzyl thioethergroup) followed by reaction a suitable nitrosylating agent, such asthionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite, suchas tert-butyl nitrite, or nitrosonium tetrafluoroborate, in a suitableanhydrous solvent, such as methylene chloride, THF, DMF, oracetonitrile, with or without an amine base, such as pyridine ortriethyl-amine, affords the compound of structure IB. Alternatively,treatment of the deprotected thiol derived from compound 3 with astoichiometric quantity of sodium nitrite in an acidic aqueous oralcoholic solution affords the compound of structure IB.

[0323] Nitro compounds of structure (I), wherein R₁, R₂, R_(e), R_(f),and p are as defined herein, and a nitrate containing imide isrepresentative of the R₃ group, as defined herein, may be prepared asshown in FIG. 3. The amide group of structure 1 is converted to theimide of structure 4, wherein p, R_(e) and R_(f) are as defined herein,and X is a halogen, by reaction with an appropriate halide containingactivated acylating agent. Preferred methods for the formation of imidesare reacting the amide with the preformed acid chloride of the halidecontaining acid in the presence of pyridine at low temperature orcondensing the amide and halide containing symmetrical anhydride in thepresence of a catalyst, such as sulfuric acid. Preferred halides arebromide and iodide. Reaction of the imide of structure 4 with a suitablenitrating agent, such as silver nitrate, in an inert solvent, such asacetonitrile, affords the compound of structure IC.

[0324] Nitroso compounds of structure (II), wherein R₈, R₉, R₁₀, R_(e),R_(f), and p are as defined herein, and a nitrite containing amide isrepresentative of the R₄ group, as defined herein, may be prepared asshown in FIG. 4. The imidazo[2,1-b]quinazoline of structure 5 isconverted to the acylimidazo[2,1-b]quinazoline of structure 6, whereinp, R_(e) and R_(f) are as defined herein, by reaction with anappropriate protected alcohol containing activated acylating agent,wherein P¹ is as defined herein. Preferred methods for the formation ofacylimidazo[2,1-b]quinazolines are reacting theimidazo[2,1-b]quinazoline with the preformed acid chloride orsymmetrical anhydride of the protected alcohol containing acid orcondensing the imidazo[2,1-b]quinazoline and protected alcoholcontaining acid in the presence of a dehydrating agent, such asdicyclohexylcarbodiimide (DCC) or 1-ethyl-3(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC.HCl) with orwithout a catalyst such as 4-dimethylamino-pyridine (DMAP) or1-hydroxybenzotriazole (HOBt). Preferred protecting groups for thealcohol moiety are silyl ethers, such as a trimethylsilyl ortertbutyldimethylsilyl ether. Deprotection of the hydroxyl moiety(fluoride ion is the preferred method for removing silyl etherprotecting groups) followed by reaction a suitable nitrosylating agent,such as thionyl chloride nitrite, thionyl dinitrite, or nitrosoniumtetrafluoroborate, in a suitable anhydrous solvent, such asdichloromethane, THF, DMF, or acetonitrile, with or without an aminebase, such as pyridine or triethylamine, affords the compound ofstructure IIA.

[0325] Nitroso compounds of structure (II), wherein R₈, R₉, R₁₀, R_(e),R_(f), and p are as defined herein, and a nitrosothiol containing amideis representative of the R₄ group, as defined herein, may be prepared asshown in FIG. 5. The imidazo[2,1-b]quinazoline of structure 5 isconverted to the acylimidazo[2,1-b]quinazoline of structure 7, whereinp, R_(e) and R_(f) are as defined herein, by reaction with anappropriate protected thiol containing activated acylating agent,wherein P² is as defined herein. Preferred methods for the formation ofacylated imidazo[2,1-b]quinazolines are reacting theimidazo[2,1-b]-quinazoline with the preformed acid chloride orsymmetrical anhydride of the protected thiol containing acid orcondensing the imidazo[2,1-b]-quinazoline and protected thiol containingacid in the presence of a dehydrating agent, such as DCC or EDAC.HClwith or without a catalyst, such as DMAP or HOBt. Preferred protectinggroups for the thiol moiety are a thioester, such as a thioacetate orthiobenzoate, a disulfide, a thiocarbamate, such as N-methoxymethylthiocarbamate, or a thioether, such as a paramethoxybenzyl thioether, atetrahydropyranyl thioether or a 2,4,6-trimethoxybenzyl thioether.Deprotection of the thiol moiety (zinc in dilute aqueous acid,triphenylphosphine in water and sodium borohydride are preferred methodsfor reducing disulfide groups while aqueous base is typically used tohydrolyze thioesters and N-methoxymethyl thiocarbamates and mercurictrifluoroacetate, silver nitrate, or strong acids, such astrifluoroacetic or hydrochloric acid, and heat are used to remove aparamethoxybenzyl thioether, a tetrahydropyranyl thioether, or a2,4,6-trimethoxybenzyl thioether group) followed by reaction with asuitable nitrosylating agent, such as thionyl chloride nitrite, thionyldinitrite, a lower alkyl nitrite, such as tert-butyl nitrite, ornitrosonium tetrafluoroborate, in a suitable anhydrous solvent, such asmethylene chloride, THF, DMF, or acetonitrile, with or without an aminebase, such as pyridine or triethylamine, affords the compound ofstructure IIB. Alternatively, treatment of the deprotected thiol derivedfrom compound 7 with a stoichiometric quantity of sodium nitrite in anacidic aqueous or alcoholic solution affords the compound of structureIIB.

[0326] Nitro compounds of structure (H), wherein R₈, R₉, R₁₀, R_(e),R_(f), and p are as defined herein, and a nitrate containing amide isrepresentative of the R₄ group, as defined herein, may be prepared asshown in FIG. 6. The imidazo[2,1-b]quinazoline of structure 5 isconverted to the acylimidazo[2,1-b]quinazoline of structure 8, whereinp, R_(e) and R_(f) are as defined herein, and X is halogen, by reactionwith an appropriate halide containing activated acylating agent.Preferred methods for the formation of theacylimidazo-[2,1-b]quinazolines are reacting theimidazo[2,1-b]quinazoline with the preformed acid chloride orsymmetrical anhydride of the halide containing acid or condensing thealcohol and halide containing acid in the presence of a dehydratingagent, such as DCC or EDAC.HCl, with or without a catalyst, such as DMAPor HOBt. Preferred halides are bromide and iodide. Reaction of theacylimidazo[2,1-b]quinazoline of structure 8 with a suitable nitratingagent, such as silver nitrate, in an inert solvent, such asacetonitrile, affords the compound of structure IIC.

[0327] Nitroso compounds of structure (III), wherein E₁, G₁, R₂₁, R₂₂,R_(e), R_(f), and p are as defined herein, and a nitrite containingamide is representative of the R₁₁ group, as defined herein, may beprepared as shown in FIG. 7. The purine-6-one group of structure 9 isconverted to the acylated purine-6-one of structure 10, wherein p, R_(e)and R_(f) are as defined herein, by reaction with an appropriateprotected alcohol containing activated acylating agent, wherein P¹ is asdefined herein. Preferred methods for the formation of acylatedpurine-6-ones are reacting the purine-6-one with the preformed acidchloride or symmetrical anhydride of the protected alcohol containingacid. Preferred protecting groups for the alcohol moiety are silylethers, such as a tertbutyldimethylsilyl ether or atert-butyldiphenylsilyl ether. Deprotection of the hydroxyl moiety(fluoride ion is the preferred method for removing silyl etherprotecting groups) followed by reaction a suitable nitrosylating agent,such as thionyl chloride nitrite, thionyl dinitrite, or nitrosoniumtetrafluoroborate, in a suitable anhydrous solvent, such asdichloromethane, THF, DMF, or acetonitrile, with or without an aminebase, such as pyridine or triethylamine, affords the compound ofstructure IIIA.

[0328] Nitroso compounds of structure (III), wherein E₁, G₁, R₂₁, R₂₂,R_(e), R_(f), and p are as defined herein, and an nitrosothiolcontaining amide is representative of the R₁₁ group, as defined herein,may be prepared as shown in FIG. 8. The purine-6-one group of structure9 is converted to the acylated purine-6-one of structure 11, wherein p,R_(e) and R_(f) are as defined herein, by reaction with an appropriateprotected thiol containing activated acylating agent, wherein P² is asdefined herein. Preferred methods for the formation of acylatedpurine-6-ones are reacting the purine-6-one with the preformed acidchloride or symmetrical anhydride of the protected alcohol containingacid. Preferred protecting groups for the thiol moiety are a thioester,such as a thioacetate, or thiobenzoate, a disulfide, a thiocarbamate,such as N-methoxymethyl thiocarbamate, or a thioether, such as aparamethoxybenzyl thioether, a tetrahydropyranyl thioether or a2,4,6-trimethoxybenzyl thioether. Deprotection of the thiol moiety (zincin dilute aqueous acid, triphenylphosphine in water and sodiumborohydride are preferred methods for reducing disulfide groups whileaqueous base is typically used to hydrolyze thioesters andN-methoxymethyl thiocarbamates and mercuric trifluoroacetate, silvernitrate, or strong acids, such as trifluoroacetic or hydrochloric acid,and heat are used to remove a paramethoxy-benzyl thioether, atetrahydropyranyl thioether, or a 2,4,6-trimethoxybenzyl thioethergroup) followed by reaction a suitable nitrosylating agent, such asthionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite, suchas tert-butyl nitrite, or nitrosonium tetrafluoroborate, in a suitableanhydrous solvent, such as methylene chloride, THF, DMF, oracetonitrile, with or without an amine base, such as pyridine ortriethylamine, affords the compound of structure IIIB. Alternatively,treatment of the deprotected thiol derived from compound 11 with astoichiometric quantity of sodium nitrite in an acidic aqueous oralcoholic solution affords the compound of structure IIIB.

[0329] Nitro compounds of structure (III), wherein E₁, G₁, R₂₁, R₂₂,R_(e), R_(f), and p are as defined herein, and a nitrate containingamide is representative of the R₁₁ group, as defined herein, may beprepared as shown in FIG. 9. The purine-6-one of structure 9 isconverted to the acylated purine-6-one of structure 12, wherein p, R_(e)and R_(f) are as defined herein and X is halogen. Preferred methods forthe formation of acylated purine-6-ones are reacting the purine-6-onewith the preformed acid chloride or symmetrical anhydride of the halidecontaining acid. Preferred halides are bromide and iodide. Reaction ofthe of the acylated purine-6-one of structure 12 with a suitablenitrating agent, such as silver nitrate, in an inert solvent, such asacetonitrile, affords the compound of structure IIIC.

[0330] Nitroso compounds of structure (IV), wherein G₂, R₈, R₁₃, R_(e),R_(f), and p are as defined herein, and a nitrite containing acylhydrazide is representative of the R₄ group, as defined herein, may beprepared as shown in FIG. 10. The 3 (2-H)-pyridazinone or2H-1,2,3,4-thiadiazine of structure 13 is converted to the 3(2-acyl)-pyridazinone or 2-acyl-1,2,3,4-thiadiazine of structure 14,wherein p, R_(e) and R_(f) are as defined herein, by reaction with anappropriate protected alcohol containing activated acylating agent,wherein P¹ is as defined herein. Preferred methods for the formation of3 (2-acyl)-pyridazinone or 2-acyl-1,2,3,4-thiadiazine are reacting the 3(2H)-pyridazinone or 2H-1,2,3,4-thiadiazine with the preformed acidchloride or symmetrical anhydride of the protected alcohol containingacid or condensing the 3 (2-H)-pyridazinone or 2H-1,2,3,4-thiadiazineand protected alcohol containing acid in the presence of a dehydratingagent, such as DCC or EDAC.HCl with a catalyst, such as DMAP or HOBt.Preferred protecting groups for the alcohol moiety are silyl ethers,such as a tert-butyldimethylsilyl ether or a tert-butyldiphenylsilylether. Deprotection of the hydroxyl moiety (fluoride ion is thepreferred method for removing silyl ether protecting groups) followed byreaction a suitable nitrosylating agent, such as thionyl chloridenitrite, thionyl dinitrite, or nitrosonium tetrafluoroborate, in asuitable anhydrous solvent, such as dichloromethane, THF, DMF, oracetonitrile, with or without an amine base, such as pyridine ortriethylamine, affords the compound of structure IVA.

[0331] Nitroso compounds of structure (IV), wherein G₂, R₈, R₁₃, R_(e),R_(f), and p are as defined herein, and a nitrosothiol containing acylhydrazide is representative of the R₄ group, as defined herein, may beprepared as shown in FIG. 11. The 3 (2-H)-pyridazinone or2H-1,2,3,4-thiadiazine of structure 13 is converted to the 3(2-acyl)-pyridazinone or 2-acyl-1,2,3,4-thiadiazine of structure 15,wherein p, R_(e) and R_(f) are as defined herein, by reaction with anappropriate protected thiol containing activated acylating agent,wherein P² is as defined herein. Preferred methods for the formation of3 (2-acyl)-pyridazinones or 2-acyl-1,2,3,4-thiadiazines are reacting the3 (2-H)-pyridazinone or 2H-1,2,3,4-thiadiazine with the preformed acidchloride or symmetrical anhydride of the protected thiol containing acidor condensing the 3 (2-H)-pyridazinone or 2H-1,2,3,4-thiadiazine andprotected thiol containing acid in the presence of a dehydrating agent,such as DCC or EDAC.HCl with a catalyst, such as DMAP or HOBt. Preferredprotecting groups for the thiol moiety are a thioester, such asthioacetate, or thiobenzoate, a disulfide, or a thioether, such asparamethoxy-benzyl thioether, tetrahydropyranyl thioether or2,4,6-trimethoxybenzyl thioether. Deprotection of the thiol moiety (zincin dilute aqueous acid, triphenylphosphine in water and sodiumborohydride are preferred methods for reducing disulfide groups whilemercuric trifluoroacetate, silver nitrate, or strong acids, such astrifluoroacetic or hydrochloric acid, and heat are used to remove aparamethoxybenzyl thioether, a tetrahydropyranyl thioether, or a2,4,6-trimethoxybenzyl thioether group) followed by reaction a suitablenitrosylating agent, such as thionyl chloride nitrite, thionyldinitrite, a lower alkyl nitrite, such as tert-butyl nitrite, ornitrosonium tetrafluoroborate, in a suitable anhydrous solvent, such asmethylene chloride, THF, DMF, or acetonitrile, with or without an aminebase, such as pyridine or triethyl amine, affords the compound ofstructure IVB. Alternatively, treatment of the deprotected thiol derivedfrom compound 15 with a stoichiometric quantity of sodium nitrite in anacidic aqueous or alcoholic solution affords the compound of structureIVB.

[0332] Nitro compounds of structure (IV), wherein G₂, R₈, R₁₃, R_(e),R_(f), and p are as defined herein, and an nitrate containing acylhydrazide is representative of the R₄ group, as defined herein, may beprepared as outlined in FIG. 12. The 3 (2-H)-pyridazinone or2H-1,2,3,4-thiadiazine of structure 13 is converted to the 3(2-acyl)-pyridazinone or 2-acyl-1,2,3,4-thiadiazine of structure 16,wherein p, R_(e) and R_(f) are as defined herein, and X is halogen.Preferred methods for the formation of 3 (2-acyl)-pyridazinones or2-acyl-1,2,3,4-thiadiazines are reacting the 3 (2-H)-pyridazinone or2H-1,2,3,4-thiadiazine with the preformed acid chloride or symmetricalanhydride of the halide containing acid or condensing the 3(2-H)-pyridazinone or 2H-1,2,3,4-thiadiazine and halide containing acidin the presence of a dehydrating agent such as DCC or EDAC.HCl with acatalyst such as DMAP or HOBt. Preferred halides are bromide and iodide.Reaction of the 3 (2-acyl)-pyridazinone or 2-acyl-1,2,3,4-thiadiazine ofstructure 16 with a suitable nitrating agent such as silver nitrate inan inert solvent such as acetonitrile affords the compound of structureIVC.

[0333] Nitroso compounds of structure (V), wherein R₁₄, R_(e), R_(f),and p are as defined herein, and an nitrite containing imide isrepresentative of the R₄ group, as defined herein, may be prepared asoutlined in FIG. 13. The amide group of structure 17 is converted to theimide of structure 18, wherein p, R_(e), and R_(f) are as definedherein, by reaction with an appropriate protected alcohol containingactivated acylating agent, wherein P¹ is as defined herein. Preferredmethods for the formation of imides are reacting the amide with thepreformed acid chloride of the protected alcohol containing acid in thepresence of pyridine at low temperature or condensing the amide andprotected alcohol containing symmetrical anhydride in the presence of acatalyst such as sulfuric acid. Preferred protecting groups for thealcohol moiety are silyl ethers such as a tert-butyldimethylsilyl etheror a tert-butyldiphenylsilyl ether. Deprotection of the hydroxyl moiety(fluoride ion is the preferred method for removing silyl etherprotecting groups) followed by reaction a suitable nitrosylating agentsuch as thionyl chloride nitrite, thionyl dinitrite, or nitrosoniumtetrafluoroborate in a suitable anhydrous solvent such asdichloro-methane, THF, DMF, or acetonitrile with or without an aminebase such as pyridine or triethylamine affords the compound of structureVA.

[0334] Nitroso compounds of structure (V), wherein R₁₄, R_(e), R_(f),and p are as defined herein, and a nitrosothiol containing imide isrepresentative of the R₄ group, as defined herein, may be prepared asoutlined in FIG. 14. The amide group of structure 17 is converted to theimide of structure 19, wherein p, R_(e) and R_(f) are as defined herein,by reaction with an appropriate protected thiol containing activatedacylating agent, wherein P² is as defined herein. Preferred methods forthe formation of imides are reacting the amide with the preformed acidchloride of the protected thiol containing acid in the presence ofpyridine at low temperature or condensing the amide and protected thiolcontaining symmetrical anhydride in the presence of a catalyst such assulfuric acid. Preferred protecting groups for the thiol moiety are as athioester such as a thioacetate or thiobenzoate, as a disulfide, as athiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioethersuch as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether ora 2,4,6-trimethoxybenzyl thioether. Deprotection of the thiol moiety(zinc in dilute aqueous acid, triphenylphosphine in water and sodiumborohydride are preferred methods for reducing disulfide groups whileaqueous base is typically used to hydrolyze thioesters andN-methoxymethyl thiocarbamates and mercuric trifluoroacetate, silvernitrate, or strong acids such as trifluoroacetic or hydrochloric acidand heat are used to remove a paramethoxybenzyl thioether, atetrahydropyranyl thioether, or a 2,4,6-trimethoxybenzyl thioethergroup) followed by reaction a suitable nitrosylating agent such asthionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite suchas tert-butyl nitrite, or nitrosonium tetrafluoroborate in a suitableanhydrous solvent such as methylene chloride, THF, DMF, or acetonitrilewith or without an amine base such as pyridine or triethylamine affordsthe compound of structure VB. Alternatively, treatment of thedeprotected thiol derived from compound 19 with a stoichiometricquantity of sodium nitrite in an acidic aqueous or alcoholic solutionaffords the compound of structure VB.

[0335] Nitro compounds of structure (V), wherein R₁₄, R_(e), R_(f), andp are as defined herein, and a nitrate containing imide isrepresentative of the R₄ group, as defined herein, may be prepared asoutlined in FIG. 15. The amide group of the formula 17 is converted tothe imide of the formula 20, wherein p, R_(e) and R_(f) are as definedherein, and X is a halogen by reaction with an appropriate halidecontaining activated acylating agent. Preferred methods for theformation of imides are reacting the amide with the preformed acidchloride of the halide containing acid in the presence of pyridine atlow temperature or condensing the amide and halide containingsymmetrical anhydride in the presence of a catalyst such as sulfuricacid. Preferred halides are bromide and iodide. Reaction of the imide ofthe formula 20 with a suitable nitrating agent such as silver nitrate inan inert solvent such as acetonitrile affords the compound of structureVC.

[0336] Nitroso compounds of structure (VI), wherein R₁₅, R₁₆, R_(e),R_(f) and p are as defined herein, and a nitrite containing acylimidazolide is representative of the R₁₇ group, as defined herein, maybe prepared as outlined in FIG. 16. The 1H-purine-2,6-dione of structure21 is converted to the acylated derivative of the formula 22, wherein p,R_(e) and R_(f) are as defined herein, by reaction with an appropriateprotected alcohol containing activated acylating agent, wherein P¹ is asdefined herein. Preferred methods for the formation of acylated1H-purine-2,6-diones are reacting the 1H-purine-2,6-dione with thepreformed acid chloride or symmetrical anhydride of the protectedalcohol containing acid or condensing the 1H-purine-2,6-dione andprotected alcohol containing acid in the presence of a dehydrating agentsuch as DCC or EDAC.HCl with a catalyst such as DMAP or HOBt. Preferredprotecting groups for the alcohol moiety are silyl ethers such as atert-butyldimethylsilyl ether or a tert-butyldimethyl-silyl ether.Deprotection of the hydroxyl moiety (fluoride ion is the preferredmethod for removing silyl ether protecting groups) followed by reactiona suitable nitrosylating agent such as thionyl chloride nitrite, thionyldinitrite, or nitrosonium tetrafluoroborate in a suitable anhydroussolvent such as dichloromethane, THF, DMF, or acetonitrile with orwithout an amine base such as pyridine or triethylamine affords thecompound of structure VIA.

[0337] Nitroso compounds of structure (VI), wherein R₁₅, R₁₆, R_(e),R_(f), and p are as defined herein, and a nitrosothiol containing acylimidazolide is representative of the R₁₇ group, as defined herein, maybe prepared as outlined in FIG. 17. The 1H-purine-2,6-dione of structure21 is converted to the acylated derivative of the formula 23, wherein p,R_(e) and R_(f) are as defined herein, by reaction with an appropriateprotected thiol containing activated acylating agent, wherein P² is asdefined herein. Preferred methods for the formation of acylated1H-purine-2,6-diones are reacting the 1H-purine-2,6-dione with thepreformed acid chloride or symmetrical anhydride of the protected thiolcontaining acid or condensing the 1H-purine-2,6-dione and protectedthiol containing acid in the presence of a dehydrating agent such as DCCor EDAC HCl with a catalyst such as DMAP or HOBt. Preferred protectinggroups for the thiol moiety are as a thioester such as a thioacetate orthiobenzoate, as a disulfide, as a thiocarbamate such as N-methoxymethylthiocarbamate, or as a thioether such as a paramethoxy-benzyl thioether,a tetrahydropyranyl thioether or a 2,4,6-trimethoxybenzyl thioether.Deprotection of the thiol moiety (zinc in dilute aqueous acid,triphenylphosphine in water and sodium borohydride are preferred methodsfor reducing disulfide groups while aqueous base is typically utilizedto hydrolyze thioesters and N-methoxymethyl thiocarbamates and mercurictrifluoroacetate, silver nitrate, or strong acids such astrifluoroacetic or hydrochloric acid and heat are used to remove aparamethoxybenzyl thioether, a tetrahydropyranyl thioether, or a2,4,6-trimethoxybenzyl thioether group) followed by reaction a suitablenitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite,a lower alkyl nitrite such as tert-butyl nitrite, or nitrosoniumtetrafluoroborate in a suitable anhydrous solvent such as methylenechloride, THF, DMF, or acetonitrile with or without an amine base suchas pyridine or triethylamine affords the compound of structure VIB.Alternatively, treatment of the deprotected thiol derived from compound23 with a stoichiometric quantity of sodium nitrite in an acidic aqueousor alcoholic solution affords the compound of structure VIB.

[0338] Nitro compounds of structure (VI), wherein R₁₅, R₁₆, R_(e),R_(f), and p are as defined herein, and an nitrate containing acylated1H-purine-2,6-dione is representative of the R₁₇ group, as definedherein, may be prepared as outlined in FIG. 18. The 1H-purine-2,6-dioneof the formula 21 is converted to the acylated derivative of the formula24, wherein p, R_(e) and R_(f) are as defined herein, and X is ahalogen, by reaction with an appropriate halide containing activatedacylating agent. Preferred methods for the formation of acylated1H-purine-2,6-diones are reacting the 1H-purine-2,6-dione with thepreformed acid chloride or symmetrical anhydride of the halidecontaining acid or condensing the 1H-purine-2,6-dione and halidecontaining acid in the presence of a dehydrating agent such as DCC orEDAC.HCl with a catalyst such as DMAP or HOBt. Preferred halides arebromide and iodide. Reaction of the acylated 1H-purine-2,6-dione of theformula 24 with a suitable nitrating agent such as silver nitrate in aninert solvent such as acetonitrile affords the compound of structureVIC.

[0339] Nitroso compounds of structure (VII), wherein R₈, R₁₈, R_(e),R_(f), and p are as defined herein, and a nitrite containing imide isrepresentative of the R₄ group, as defined herein, may be prepared asoutlined in FIG. 19. The amide nitrogen of structure 25 is converted tothe imide of structure 26, wherein p, R_(e) and R_(f) are as definedherein, by reaction with an appropriate protected alcohol containingactivated acylating agent, wherein P¹ is as defined herein. Preferredmethods for the formation of imides are reacting the amide with thepreformed acid chloride of the protected alcohol containing acid in thepresence of pyridine at low temperature or condensing the amide andprotected alcohol containing symmetrical anhydride in the presence of acatalyst such as sulfuric acid. Preferred protecting groups for thealcohol moiety are silyl ethers such as a tert-butyldimethylsilyl etheror a tertbutyldiphenylsilyl ether. Deprotection of the hydroxyl moiety(fluoride ion is the preferred method for removing silyl etherprotecting groups) followed by reaction a suitable nitrosylating agentsuch as thionyl chloride nitrite, thionyl dinitrite, or nitrosoniumtetrafluoroborate in a suitable anhydrous solvent such asdichloromethane, THF, DMF, or acetonitrile with or without an amine basesuch as pyridine or triethylamine affords the compound of structureVIIA.

[0340] Nitroso compounds of structure (VII), wherein R₈, R₁₈, R_(e),R_(f), and p are as defined herein, and a nitrosothiol containing imideis representative of the R₄ group, as defined herein, may be prepared asoutlined in FIG. 20. The amide nitrogen of structure 25 is converted tothe imide of structure 27, wherein p, R_(e) and R_(f) are as definedherein, by reaction with an appropriate protected thiol containingactivated acylating agent, wherein P² is as defined herein. Preferredmethods for the formation of imides are reacting the amide with thepreformed acid chloride of the protected thiol containing acid in thepresence of pyridine at low temperature or condensing the amide andprotected thiol containing symmetrical anhydride in the presence of acatalyst such as sulfuric acid. Preferred protecting groups for thethiol moiety are as a thioester such as a thioacetate or thiobenzoate,as a disulfide, as a thiocarbamate such as N-methoxymethylthiocarbamate, or as a thioether such as a paramethoxybenzyl thioether,a tetrahydropyranyl thioether or a 2,4,6-trimethoxybenzyl thioether.Deprotection of the thiol moiety (zinc in dilute aqueous acid,triphenylphosphine in water and sodium borohydride are preferred methodsfor reducing disulfide groups while aqueous base is typically used tohydrolyze thioesters and N-methoxymethyl thiocarbamates and mercurictrifluoroacetate, silver nitrate, or strong acids such astrifluoroacetic or hydrochloric acid and heat are used to remove aparamethoxybenzyl thioether, a tetrahydropyranyl thioether, or a2,4,6-trimethoxybenzyl thioether group) followed by reaction a suitablenitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite,a lower alkyl nitrite such as tert-butyl nitrite, or nitrosoniumtetrafluoroborate in a suitable anhydrous solvent such as methylenechloride, THF, DMF, or acetonitrile with or without an amine base suchas pyridine or triethylamine affords the compound of structure VIIB.Alternatively, treatment of the deprotected thiol derived from compound27 with a stoichiometric quantity of sodium nitrite in an acidic aqueousor alcoholic solution affords the compound of structure VIIB.

[0341] Nitro compounds of structure (VII), wherein R₈, R₁₈, R_(e),R_(f), and p are as defined herein, and a nitrate containing imide isrepresentative of the R₄ group, as defined herein, may be prepared asoutlined in FIG. 21. The amide group of the formula 25 is converted tothe imide of the formula 28, wherein p, R_(e) and R_(f) are as definedherein, and X is a halogen, by reaction with an appropriate halidecontaining activated acylating agent. Preferred methods for theformation of imides are reacting the amide with the preformed acidchloride of the halide containing acid in the presence of pyridine atlow temperature or condensing the amide and halide containingsymmetrical anhydride in the presence of a catalyst such as sulfuricacid. Preferred halides are bromide and iodide. Reaction of the imide ofthe formula 28 with a suitable nitrating agent such as silver nitrate inan inert solvent such as acetonitrile affords the compound of structureVIIC.

[0342] Nitroso compounds of structure (VIII), wherein R_(e) R_(f), and pare as defined herein, and a nitrite containing imide is representativeof the R₁₉ group, as defined herein, may be prepared as outlined in FIG.22. The amide nitrogen of structure 29 is converted to the imide ofstructure 30, wherein p, R_(e) and R_(f) are as defined herein, byreaction with an appropriate protected alcohol containing activatedacylating agent, wherein P¹ is as defined herein. Preferred methods forthe formation of imides are reacting the amide with the preformed acidchloride of the protected alcohol containing acid in the presence ofpyridine at low temperature or condensing the amide and protectedalcohol containing symmetrical anhydride in the presence of a catalyst,such as sulfuric acid. Preferred protecting groups for the alcoholmoiety are silyl ethers such as a tert-butyldimethylsilyl ether or atert-butyldiphenylsilyl ether. Deprotection of the hydroxyl moiety(fluoride ion is the preferred method for removing silyl etherprotecting groups) followed by reaction a suitable nitrosylating agentsuch as thionyl chloride nitrite, thionyl dinitrite, or nitrosoniumtetrafluoroborate in a suitable anhydrous solvent such asdichloromethane, THF, DMF, or acetonitrile, with or without an aminebase, such as pyridine or triethylamine, affords the compound ofstructure VIIIA.

[0343] Nitroso compounds of structure (VIII), wherein R_(e), R_(f), andp are as defined herein, and a nitrosothiol containing imide isrepresentative of the R₁₉ group, as defined herein, may be prepared asoutlined in FIG. 23. The amide nitrogen of structure 29 is converted tothe imide of structure 31, wherein p, R_(e) and R_(f) are as definedherein, by reaction with an appropriate protected thiol containingactivated acylating agent, wherein P² is as defined herein. Preferredmethods for the formation of imides are reacting the amide with thepreformed acid chloride of the protected thiol containing acid in thepresence of pyridine at low temperature or condensing the amide andprotected alcohol containing symmetrical anhydride in the presence of acatalyst such as sulfuric acid. Preferred protecting groups for thethiol moiety are as a thioester such as a thioacetate or thiobenzoate,as a disulfide, as a thiocarbamate such as N-methoxymethylthiocarbamate, or as a thioether such as a paramethoxybenzyl thioether,a tetrahydropyranyl thioether or a 2,4,6-trimethoxybenzyl thioether.Deprotection of the thiol moiety (zinc in dilute aqueous acid,triphenylphosphine in water and sodium borohydride are preferred methodsfor reducing disulfide groups while aqueous base is typically utilizedto hydrolyze thioesters and N-methoxymethyl thiocarbamates and mercurictrifluoroacetate, silver nitrate, or strong acids such astrifluoroacetic or hydrochloric acid and heat are used to remove aparamethoxybenzyl thioether, a tetrahydropyranyl thioether, or a2,4,6-trimethoxybenzyl thioether group) followed by reaction a suitablenitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite,a lower alkyl nitrite such as tert-butyl nitrite, or nitrosoniumtetrafluoroborate in a suitable anhydrous solvent such as methylenechloride, THF, DMF, or acetonitrile with or without an amine base suchas pyridine or triethylamine affords the compound of structure VIIB.Alternatively, treatment of the deprotected thiol derived from compound31 with a stoichiometric quantity of sodium nitrite in an acidic aqueousor alcoholic solution affords the compound of structure VIIIB.

[0344] Nitro compounds of structure (VIII), wherein R_(e) R_(f), and pare as defined herein, and a nitrate containing imide is representativeof the R₁₉ group, as defined herein, may be prepared as outlined in FIG.24. The amide group of the formula 29 is converted to the imide of theformula 32, wherein p, R_(e) and R_(f) are as defined herein, and X is ahalogen, by reaction with an appropriate halide containing activatedacylating agent. Preferred methods for the formation of imides arereacting the amide with the preformed acid chloride of the halidecontaining acid in the presence of pyridine at low temperature orcondensing the amide and halide containing symmetrical anhydride in thepresence of a catalyst such as sulfuric acid. Preferred halides arebromide and iodide. Reaction of the imide of the formula 32 with asuitable nitrating agent such as silver nitrate in an inert solvent suchas acetonitrile affords the compound of structure VIIIC.

[0345] Nitroso compounds of structure (IX), wherein R₂₀, R_(e), R_(f),and p are as defined herein, and an nitrite containing acylated amide orsulfonamide is representative of the R₄ group, as defined herein, may beprepared as outlined in FIG. 25. The amide or sulfonamide nitrogen ofstructure 33 is converted to the N-acylated derivative of structure 34,wherein p, R_(e) and R_(f) are as defined herein, by reaction with anappropriate protected alcohol containing activated acylating agent,wherein P¹ is as defined herein. Preferred methods for the formation ofacylated amides or sulfonamides are reacting the amide or sulfonamidewith the preformed acid chloride of the protected alcohol containingacid in the presence of pyridine at low temperature or condensing theamide or sulfonamide and protected alcohol containing symmetricalanhydride in the presence of a catalyst such as sulfuric acid. Preferredprotecting groups for the alcohol moiety are silyl ethers such as atert-butyldimethylsilyl ether or a tertbutyldiphenylsilyl ether.Deprotection of the hydroxyl moiety (fluoride ion is the preferredmethod for removing silyl ether protecting groups) followed by reactiona suitable nitrosylating agent such as thionyl chloride nitrite, thionyldinitrite, or nitrosonium tetrafluoroborate in a suitable anhydroussolvent such as dichloromethane, THF, DMF, or acetonitrile with orwithout an amine base such as pyridine or triethylamine affords thecompound of structure IXA.

[0346] Nitroso compounds of structure (IX), wherein R₂₀, R_(e), R_(f),and p are as defined herein, and an nitrosothiol containing acylatedamide or sulfonamide is representative of the R₄ group, as definedherein, may be prepared as outlined in FIG. 26. The amide or sulfonamidenitrogen of structure 33 is converted to the N-acylated derivative ofstructure 35, wherein p, R_(e) and R_(f) are as defined herein, byreaction with an appropriate protected thiol containing activatedacylating agent, wherein P² is as defined herein. Preferred methods forthe formation of acylated amides or sulfonamides are reacting the amideor sulfonamide with the preformed acid chloride of the protected thiolcontaining acid in the presence of pyridine at low temperature orcondensing the amide or sulfonamide and protected thiol containingsymmetrical anhydride in the presence of a catalyst such as sulfuricacid. Preferred protecting groups for the thiol moiety are as athioester such as a thioacetate or thiobenzoate, as a disulfide, as athiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioethersuch as a paramethoxy-benzyl thioether, a tetrahydropyranyl thioether ora 2,4,6-trimethoxybenzyl thioether. Deprotection of the thiol moiety(zinc in dilute aqueous acid, triphenylphosphine in water and sodiumborohydride are preferred methods for reducing disulfide groups whileaqueous base is typically utilized to hydrolyze thioesters andN-methoxymethyl thiocarbamates and mercuric trifluoroacetate, silvernitrate, or strong acids such as trifluoroacetic or hydrochloric acidand heat are used to remove a paramethoxybenzyl thioether, atetrahydropyranyl thioether, or a 2,4,6-trimethoxybenzyl thioethergroup) followed by reaction a suitable nitrosylating agent such asthionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite suchas tert-butyl nitrite, or nitrosonium tetrafluoroborate in a suitableanhydrous solvent such as methylene chloride, THF, DMF, or acetonitrilewith or without an amine base such as pyridine or triethylamine affordsthe compound of structure IXB. Alternatively, treatment of thedeprotected thiol derived from compound 35 with a stoichiometricquantity of sodium nitrite in an acidic aqueous or alcoholic solutionaffords the compound of structure IXB.

[0347] Nitro compounds of structure (IX), wherein R₂₀, R_(e) R_(f), andp are as defined herein, and a nitrate containing acylated amide orsulfonamide is representative of the R₄ group, as defined herein, may beprepared as outlined in FIG. 27. The amide or sulfonamide group of theformula 33 is converted to the N-acylated derivative of the formula 36,wherein p, R_(e) and R_(f) are as defined herein, and X is a halogen, byreaction with an appropriate halide containing activated acylatingagent. Preferred methods for the formation of acylated amides orsulfonamides are reacting the amide or sulfonamide with the preformedacid chloride of the halide containing acid in the presence of pyridineat low temperature or condensing the amide or sulfonamide and halidecontaining symmetrical anhydride in the presence of a catalyst such assulfuric acid. Preferred halides are bromide and iodide. Reaction of theimide or sulfonamide of the formula 36 with a suitable nitrating agentsuch as silver nitrate in an inert solvent such as acetonitrile affordsthe compound of structure IXC.

[0348] Nitroso compounds of structure (X), wherein D₁, R_(e), R_(f), andp are as defined herein, and a nitrite containing ester isrepresentative of the D group, as defined herein, may be preparedaccording to FIG. 28. The alcohol group of structure 37 is converted tothe ester of structure 38, wherein p, R_(e) and R are as defined herein,by reaction with an appropriate protected alcohol containing activatedacylating agent, wherein P¹ is as defined herein. Preferred methods forthe formation of esters are reacting the alcohol with the preformed acidchloride or symmetrical anhydride of the protected alcohol containingacid or condensing the alcohol and protected alcohol containing acidwith a dehydrating agent such as DCC or EDAC.HCl in the presence of acatalyst such as DMAP or HOBt. Preferred protecting groups for thealcohol moiety are silyl ethers such as a trimethylsilyl or atert-butyldimethylsilyl ether. Deprotection of the hydroxyl moiety(fluoride ion is the preferred method for removing silyl etherprotecting groups) followed by reaction a suitable nitrosylating agentsuch as thionyl chloride nitrite, thionyl dinitrite, or nitrosoniumtetrafluoroborate in a suitable anhydrous solvent such asdichloromethane, THF, DMF, or acetonitrile with or without an amine basesuch as pyridine or triethylamine affords the compound of structure XA.

[0349] Nitroso compounds of structure (X), wherein D₁, R_(e) R_(f), andp are as defined herein, and a nitrosothiol containing ester isrepresentative of the D group, as defined herein, may be prepared asshown in FIG. 29. The alcohol group of structure 37 is converted to theester of structure 39, wherein p, R_(e) and R_(f) are as defined herein,by reaction with an appropriate protected thiol containing activatedacylating agent, wherein P² is as defined herein. Preferred methods forthe formation of esters are reacting the alcohol with the preformed acidchloride or symmetrical anhydride of the protected thiol containing acidor condensing the alcohol and protected thiol containing acid with adehydrating agent such as DCC or EDAC.HCl in the presence of a catalystsuch as DMAP or HOBt. Preferred protecting groups for the thiol moietyare as a thioester such as a thioacetate or thiobenzoate, as adisulfide, as a thiocarbamate such as N-methoxymethyl thiocarbamate, oras a thioether such as a paramethoxybenzyl thioether, atetrahydropyranyl thioether or a S-triphenylmethyl thioether.Deprotection of the thiol moiety (zinc in dilute aqueous acid,triphenyl-phosphine in water and sodium borohydride are preferredmethods for reducing disulfide groups while aqueous base is typicallyutilized to hydrolyze thioesters and N-methoxymethyl thiocarbamates andmercuric trifluoroacetate, silver nitrate, or strong acids such astrifluoroacetic or hydrochloric acid and heat are used to remove aparamethoxybenzyl thioether, a tetrahydropyranyl thioether or aS-triphenylmethyl thioether group) followed by reaction a suitablenitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite,a lower alkyl nitrite such as tert-butyl nitrite, or nitrosiumtetrafluoroborate in a suitable anhydrous solvent such as methylenechloride, THF, DMF, or acetonitrile with or without an amine base suchas pyridine or triethylamine affords the compound of structure XB.Alternatively, treatment of the deprotected thiol derived from compound39 with a stoichiometric quantity of sodium nitrite in aqueous oralcoholic acid affords the compound of structure XB.

[0350] Nitro compounds of structure (X), wherein D₁, R_(e), R_(f), and pare as defined herein, and a nitrate containing ester is representativeof the D group, as defined herein, may be prepared according to FIG. 30.The alcohol group of the formula 37 is converted to the ester of theformula 40, wherein p, R_(e) and R_(f) are as defined herein, and X is ahalogen, by reaction with an appropriate halide containing activatedacylating agent. Preferred methods for the formation of esters arereacting the alcohol with the preformed acid chloride or symmetricalanhydride of the halide containing acid or condensing the alcohol andhalide containing acid with a dehydrating agent such as DCC or EDAC.HClin the presence of a catalyst such as DMAP or HOBt. Preferred halidesare bromide and iodide. Reaction of the ester of the formula 40 with asuitable nitrating agent such as silver nitrate in an inert solvent suchas acetonitrile affords the compound of structure XC.

[0351] Nitroso compounds of structure (XI), wherein D₂, R_(e), R_(f),and p are as defined herein, and a nitrite containing ester isrepresentative of the D group, as defined herein, may be preparedaccording to FIG. 31. The alcohol group of structure 41 is converted tothe ester of structure 42, wherein p, R_(e) and R_(f) are as definedherein, by reaction with an appropriate protected alcohol containingactivated acylating agent, wherein P¹ is as defined herein. Preferredmethods for the formation of esters are reacting the alcohol with thepreformed acid chloride or symmetrical anhydride of the protectedalcohol containing acid or condensing the alcohol and protected alcoholcontaining acid with a dehydrating agent, such as DCC or EDAC.HCl, inthe presence of a catalyst, such as DMAP or HOBt. Preferred protectinggroups for the alcohol moiety are silyl ethers, such as a trimethylsilylor a tert-butyldimethylsilyl ether. Deprotection of the hydroxyl moiety(fluoride ion is the preferred method for removing silyl etherprotecting groups) followed by reaction a suitable nitrosylating agent,such as thionyl chloride nitrite, thionyl dinitrite, or nitrosoniumtetrafluoroborate, in a suitable anhydrous solvent, such asdichloromethane, THF, DMF, or acetonitrile, with or without an aminebase, such as pyridine or triethylamine, affords the compound ofstructure XIA.

[0352] Nitroso compounds of structure (XI), wherein D₂, R_(e) R_(f), andp are as defined herein, and a nitrosothiol containing ester isrepresentative of the D group, as defined herein, may be preparedaccording to FIG. 32. The alcohol group of structure 41 is converted tothe ester of structure 43, wherein p, R_(e) and R_(f) are as definedherein, by reaction with an appropriate protected thiol containingactivated acylating agent, wherein P² is as defined herein. Preferredmethods for the formation of esters are reacting the alcohol with thepreformed acid chloride or symmetrical anhydride of the protected thiolcontaining acid or condensing the alcohol and protected thiol containingacid with a dehydrating agent, such as DCC or EDAC.HCl, in the presenceof a catalyst, such as DMAP or HOBt. Preferred protecting groups for thethiol moiety are as a thioester, such as a thioacetate or thiobenzoate,as a disulfide, as a thiocarbamate, such as N-methoxymethylthiocarbamate, or as a thioether, such as a paramethoxybenzyl thioether,a tetrahydropyranyl thioether or a S-triphenylmethyl thioether.Deprotection of the thiol moiety (zinc in dilute aqueous acid,triphenyl-phosphine in water and sodium borohydride are preferredmethods for reducing disulfide groups while aqueous base is typicallyutilized to hydrolyze thioesters and N-methoxymethyl thiocarbamates andmercuric trifluoroacetate, silver nitrate, or strong acids, such astrifluoroacetic or hydrochloric acid, and heat are used to remove aparamethoxybenzyl thioether, a tetrahydropyranyl thioether or aS-triphenylmethyl thioether group) followed by reaction a suitablenitrosylating agent, such as thionyl chloride nitrite, thionyldinitrite, a lower alkyl nitrite, such as tert-butyl nitrite, ornitrosium tetrafluoroborate, in a suitable anhydrous solvent, such asmethylene chloride, THF, DMF, or acetonitrile, with or without an aminebase, such as pyridine or triethylamine, affords the compound ofstructure XIB. Alternatively, treatment of the deprotected thiol derivedfrom compound 43 with a stoichiometric quantity of sodium nitrite inaqueous or alcoholic acid affords the compound of structure XIB.

[0353] Nitro compounds of structure (XI), wherein D₂, R_(e), R_(f), andp are as defined herein, and a nitrate containing ester isrepresentative of the D group, as defined herein, may be preparedaccording to FIG. 33. The alcohol group of the formula 41 is convertedto the ester of the formula 44, wherein p, R_(e) and R_(f) are asdefined herein, and X is a halogen, by reaction with an appropriatehalide containing activated acylating agent. Preferred methods for theformation of esters are reacting the alcohol with the preformed acidchloride or symmetrical anhydride of the halide containing acid orcondensing the alcohol and halide containing acid with a dehydratingagent, such as DCC or EDAC.HCl, in the presence of a catalyst, such asDMAP or HOBt. Preferred halides are bromide and iodide. Reaction of theester of the formula 44 with a suitable nitrating agent, such as silvernitrate, in an inert solvent, such as acetonitrile, affords the compoundof structure XIC.

[0354] Nitroso compounds of structure (XII), wherein R_(e), R_(f), A₁,A₂, A₃, J, V and p are as defined herein, and a nitrite containingthioester is representative of the R₂₄ group, as defined herein, may beprepared according to FIG. 34. The carboxylic acid group of structure 45is converted to the thioester of structure 46, wherein p, R_(e) andR_(f) are as defined herein, by reaction with an appropriate protectedalcohol containing thiol agent, wherein P¹ is as defined herein.Preferred methods for the formation of thioesters are reacting the thiolwith the preformed acid chloride or symmetrical anhydride of thecarboxylic acid or condensing the thiol and carboxylic acid with adehydrating agent, such as DCC or EDAC.HCl, in the presence of acatalyst, such as DMAP or HOBt. Preferred protecting groups for thealcohol moiety are silyl ethers, such as a trimethylsilyl or atert-butyldimethylsilyl ether. Deprotection of the hydroxyl moiety(fluoride ion is the preferred method for removing silyl etherprotecting groups) followed by reaction a suitable nitrosylating agent,such as thionyl chloride nitrite, thionyl dinitrite, or nitrosoniumtetrafluoroborate, in a suitable anhydrous solvent, such asdichloromethane, THF, DMF, or acetonitrile, with or without an aminebase, such as pyridine or triethylamine, affords the compound ofstructure XIIA.

[0355] Nitroso compounds of structure (XII), wherein R_(e), R_(f), A₁,A₂, A₃, J, V and p are as defined herein, and a nitrosothiol containingthioester is representative of the R₂₄ group, as defined herein, may beprepared according to FIG. 35. The carboxylic acid group of structure 45is converted to the thioester of structure 47, wherein p, R_(e) andR_(f) are as defined herein, by reaction with an appropriate monoprotected dithiol. Preferred methods for the formation of thioesters arereacting the free thiol with the preformed acid chloride or symmetricalanhydride of the carboxylic acid or condensing the free thiol andcarboxylic acid with a dehydrating agent, such as DCC or EDAC.HCl, inthe presence of a catalyst, such as DMAP or HOBt. Preferred protectinggroups for the thiol moiety are as a thioester, such as a thioacetate orthiobenzoate, as a disulfide, as a thiocarbamate, such asN-methoxymethyl thiocarbamate, or as a thioether, such as aparamethoxybenzyl thioether, a tetrahydropyranyl thioether or aS-triphenylmethyl thioether. Deprotection of the thiol moiety (zinc indilute aqueous acid, triphenyl-phosphine in water and sodium borohydrideare preferred methods for reducing disulfide groups while aqueous baseis typically utilized to hydrolyze thioesters and N-methoxymethylthiocarbamates and mercuric trifluoroacetate, silver nitrate, or strongacids, such as trifluoroacetic or hydrochloric acid, and heat are usedto remove a paramethoxybenzyl thioether, a tetrahydropyranyl thioetheror a S-triphenylmethyl thioether group). Reaction of the free thiol witha suitable nitrosylating agent, such as thionyl chloride nitrite,thionyl dinitrite, a lower alkyl nitrite, such as tert-butyl nitrite, ornitrosium tetrafluoroborate, in a suitable anhydrous solvent, such asmethylene chloride, THF, DMF, or acetonitrile, with or without an aminebase, such as pyridine or triethylamine, affords the compound ofstructure XIIB. Alternatively, treatment of the deprotected thiolderived from compound 47 with a stoichiometric quantity of sodiumnitrite in aqueous or alcoholic acid affords the compound of structureXIIB.

[0356] Nitro compounds of structure (XII), wherein R_(e), R_(f), A₁, A₂,A₃, J, V and p are as defined herein, and a nitrate containing thioesteris representative of the R₂₄ group, as defined herein, may be preparedaccording to FIG. 36. The carboxylic acid group of the formula 45 isconverted to the thioester of structure 46, wherein p, R_(e) and R_(f)are as defined herein, by reaction with an appropriate protected alcoholcontaining thiol agent, wherein P¹ is as defined herein. Preferredmethods for the formation of thioesters are reacting the thiol with thepreformed acid chloride or symmetrical anhydride of the carboxylic acidor condensing the thiol and carboxylic acid with a dehydrating agent,such as DCC or EDAC.HCl, in the presence of a catalyst, such as DMAP orHOBt. Preferred protecting groups for the alcohol moiety are silylether, such as trimethylsilyl or a tert-butyldimethylsilyl ether.Deprotection of the hydroxyl moiety (fluoride ion is the preferredmethod for removing silyl ether protecting groups) followed by reactionof the alcohol with a suitable nitrating agent, such as nitric acid andacetic anhydride in ethyl acetate/acetic acid affords the compound ofstructure XIIC. Alternatively, the carboxylic acid group of structure 45is converted to the thioester of structure 48, wherein p, R_(e) andR_(f) are as defined herein, and X is halogen, by reaction with anappropriate halide containing thiol. Preferred methods for the formationof thioesters are reacting the thiol with the preformed acid chloride orsymmetrical anhydride of the carboxylic acid or condensing the thiol andcarboxylic acid with a dehydrating agent, such as DCC or EDAC.HCl, inthe presence of a catalyst, such as DMAP or HOBt. Preferred halides arebromide and iodide. Reaction of the ester of structure 48 with asuitable nitrating agent, such as silver nitrate in an inert solvent,such as acetonitrile, affords the compound of structure XIIC.

[0357] Nitroso compounds of structure (XIII), wherein R_(e), R_(f), R₃₁,R₃₂, and p are as defined herein, and a nitrite containing ester isrepresentative of the D group, as defined herein, may be preparedaccording to FIG. 37. The carboxylic acid group of structure 49 isconverted to the ester of structure 50, wherein p, R_(e) and R are asdefined herein, by reaction with a monoprotected diol, wherein P¹ is asdefined herein. Preferred methods for the formation of esters arereacting the alcohol with the preformed acid chloride or symmetricalanhydride of the carboxylic acid or condensing the alcohol andcarboxylic acid with a dehydrating agent, such as DCC or EDAC.HCl, inthe presence of a catalyst, such as DMAP or HOBt. Preferred protectinggroups for the alcohol moiety are silyl ethers, such as a trimethylsilylor a tert-butyldimethylsilyl ether. Deprotection of the hydroxyl moiety(fluoride ion is the preferred method for removing silyl etherprotecting groups) followed by reaction a suitable nitrosylating agent,such as thionyl chloride nitrite, thionyl dinitrite, or nitrosoniumtetrafluoroborate, in a suitable anhydrous solvent, such asdichloromethane, THF, DMF, or acetonitrile, with or without an aminebase, such as pyridine or triethylamine, affords the compound ofstructure XIIIA.

[0358] Nitroso compounds of structure (XIII), wherein R_(e), R_(f), R₃₁,R₃₂, and p are as defined herein, and a nitrosothiol containing ester isrepresentative of the D group, as defined herein, may be preparedaccording to FIG. 38. The carboxylic acid group of structure 49 isconverted to the ester of structure 51, wherein p, R_(e) and R_(f) areas defined herein, by reaction with an appropriate protected thiolcontaining alcohol. Preferred methods for the formation of esters arereacting the alcohol with the preformed acid chloride or symmetricalanhydride of the carboxylic acid or condensing the primary thiol andcarboxylic acid with a dehydrating agent, such as DCC or EDAC.HCl, inthe presence of a catalyst, such as DMAP or HOBt. Preferred protectinggroups for the thiol moiety are as a thioester, such as a thioacetate orthiobenzoate, as a disulfide, as a thiocarbamate, such asN-methoxymethyl thiocarbamate, or as a thioether, such as aparamethoxybenzyl thioether, a tetrahydropyranyl thioether or aS-triphenylmethyl thioether. Deprotection of the thiol moiety (zinc indilute aqueous acid, triphenyl-phosphine in water and sodium borohydrideare preferred methods for reducing disulfide groups while aqueous baseis typically utilized to hydrolyze thioesters and N-methoxymethylthiocarbamates and mercuric trifluoroacetate, silver nitrate, or strongacids, such as trifluoroacetic or hydrochloric acid, and heat are usedto remove a paramethoxybenzyl thioether, a tetrahydropyranyl thioetheror a S-triphenylmethyl thioether group) Reaction of the free thiol witha suitable nitrosylating agent, such as thionyl chloride nitrite,thionyl dinitrite, a lower alkyl nitrite, such as tert-butyl nitrite, ornitrosium tetrafluoroborate, in a suitable anhydrous solvent, such asmethylene chloride, THF, DMF, or acetonitrile, with or without an aminebase, such as pyridine or triethylamine, affords the compound ofstructure XIIIB. Alternatively, treatment of the deprotected thiolderived from compound 51 with a stoichiometric quantity of sodiumnitrite in aqueous or alcoholic acid affords the compound of structureXIIIB.

[0359] Nitro compounds of structure (XIII), wherein R_(e), R_(f), R₃₁,R₃₂ and p are as defined herein, and a nitrate containing ester isrepresentative of the D group, as defined herein, may be preparedaccording to FIG. 39. The carboxylic acid group of the formula 49 isconverted to the ester of structure 50, wherein p, R_(e) and R_(f) areas defined herein, by reaction with an appropriate mono-protected diol,wherein P¹ is as defined herein. Preferred methods for the formation ofesters are reacting the alcohol with the preformed acid chloride orsymmetrical anhydride of the carboxylic acid or condensing the alcoholand carboxylic acid with a dehydrating agent, such as DCC or EDAC.HCl,in the presence of a catalyst, such as DMAP or HOBt. Preferredprotecting groups for the alcohol moiety are silyl ether, such astrimethylsilyl or a tert-butyldimethylsilyl ether. Deprotection of thehydroxyl moiety (fluoride ion is the preferred method for removing silylether protecting groups) followed by reaction of the alcohol with asuitable nitrating agent, such as nitric acid and acetic anhydride inethyl acetate/acetic acid affords the compound of structure XIIIC.Alternatively, the carboxylic acid group of structure 49 is converted tothe ester of structure 52, wherein p, R_(e) and R_(f) are as definedherein, and X is halogen, by reaction with an appropriate halidecontaining alcohol. Preferred methods for the formation of esters arereacting the alcohol with the preformed acid chloride or symmetricalanhydride of the halide containing acid or condensing the alcohol andhalide containing alcohol with a dehydrating agent, such as DCC orEDAC.HCl in the presence of a catalyst, such as DMAP or HOBt. Preferredhalides are bromide and iodide. Reaction of the ester of structure 52with a suitable nitrating agent, such as silver nitrate in an inertsolvent, such as acetonitrile, affords the compound of structure XIIIC.

[0360] Nitroso compounds of structure (XIV), wherein R_(e), R_(f), R₃₅,R₃₆, R₃₇, R₃₈, D₁ and p are as defined herein, a carbonyl group isrepresentative of the A group, as defined herein, and a nitritecontaining substituent is representative of the R₃₄ group, as definedherein, may be prepared according to FIG. 40. The methyl9a-methyl-1,2,3,4,4a,9a-hexahydrobeta-carboline-3-carboxylate ofstructure 53 is converted to the acylated derivative of the formula 54,wherein p, R₃₅ and R₃₆ are as defined herein, oxygen is representativeof G₄, as defined herein, by reaction with an appropriate α-halocontaining activated acylating agent, wherein X is preferably chlorineor bromine. Preferred methods for the formation of N-acylated1,2,3,4,4a,9a-hexahydrobeta-carboline-3-carboxylate esters are reactingthe 1,2,3,4,4a,9a-hexahydrobeta-carboline-3-carboxylate ester with thepreformed acid chloride or symmetrical anhydride of the α-halocontaining acid or condensing the1,2,3,4,4a,9a-hexahydrobeta-carboline-3-carboxylate ester and α-halocontaining acid in the presence of a dehydrating agent such as DCC orEDAC.HCl with a catalyst such as DMAP or HOBt. Hydrolysis of the esteraffords the carboxylic acid followed by subsequent reaction with ahydroxy protected primary amino containing alcohol, wherein P¹ is asdefined herein, affords the compound of structure 55. Preferred methodsfor the formation of amides are reacting the amine with the preformedacid chloride or symmetrical anhydride of the carboxylic acid orcondensing the amine and carboxylic acid with a dehydrating agent, suchas DCC or EDAC.HCl, in the presence of a catalyst, such as DMAP or HOBt.Preferred protecting groups for the alcohol moiety are silyl ethers,such as a trimethylsilyl or a tert-butyldimethylsilyl ether. A preferredmethod for facilitating the cyclization to the afford the3,6,17-triaza-1-methyltetracyclo[8.7.0.0<3,8>0.0<11,16>]heptadeca-11(16),12,14-triene-4,7-dioneis to heat the α-halo diamide intermediate in an inert solvent such asmethanol. Deprotection of the hydroxyl moiety (fluoride ion is thepreferred method for removing silyl ether protecting groups) followed byreaction with a stoichometric quantity of a suitable nitrosylatingagent, such as thionyl chloride nitrite, thionyl dinitrite, ornitrosonium tetrafluoroborate, in a suitable anhydrous solvent, such asdichloromethane, THF, DMF, or acetonitrile, with or without an aminebase, such as pyridine or triethylamine, affords the compound ofstructure XIVA.

[0361] Nitroso compounds of structure (XIV), wherein R_(e), R_(f), R₃₅,R₃₆, R₃₇, R₃₈, D₁ and p are as defined herein, a carbonyl group isrepresentative of the A group, as defined herein, oxygen isrepresentative of G₄, as defined herein, and a nitrosothiol containingsubstituent is representative of the R₃₄ group, as defined herein, maybe prepared according to FIG. 41. Hydrolysis of the ester of thecompound of structure 54 affords the carboxylic acid which is reactedwith a sulfanyl protected primary amino containing thiol, wherein P² isas defined herein, to afford the compound of structure 56. Preferredmethods for the formation of amides are reacting the amine with thepreformed acid chloride or symmetrical anhydride of the carboxylic acidor condensing the amine and carboxylic acid with a dehydrating agent,such as DCC or EDAC.HCl, in the presence of a catalyst, such as DMAP orHOBt. Preferred protecting groups for the thiol moiety are as athioester such as a thioacetate or thiobenzoate, as a disulfide, as athiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioethersuch as a paramethoxy-benzyl thioether, a tetrahydropyranyl thioether ora 2,4,6-trimethoxybenzyl thioether. A preferred method for facilitatingthe cyclization to the afford the3,6,17-triaza-1-methyltetracyclo[8.7.0.0<3,8>0.0<11,16>]heptadeca-11(16),12,14-triene-4,7-dioneis to heat the α-halo diamide intermediate wherein X is preferablychlorine or bromine in an inert solvent such as methanol. Deprotectionof the sulfanyl moiety (zinc in dilute aqueous acid, triphenylphosphinein water and sodium borohydride are preferred methods for reducingdisulfide groups while aqueous base is typically utilized to hydrolyzethioesters and N-methoxymethyl thiocarbamates and mercurictrifluoroacetate, silver nitrate, or strong acids such astrifluoroacetic or hydrochloric acid and heat are used to remove aparamethoxybenzyl thioether, a tetrahydropyranyl thioether, or a2,4,6-trimethoxybenzyl thioether group) followed by reaction with astoichometric quantity of a suitable nitrosylating agent such as thionylchloride nitrite, thionyl dinitrite, a lower alkyl nitrite such astert-butyl nitrite, or nitrosonium tetrafluoroborate in a suitableanhydrous solvent such as methylene chloride, THF, DMF, or acetonitrilewith or without an amine base such as pyridine or triethylamine affordsthe compound of structure XIB. Alternatively, treatment of thedeprotected thiol derived from compound 55 with a stoichiometricquantity of sodium nitrite in an acidic aqueous or alcoholic solutionaffords the compound of structure XIVB.

[0362] Nitro compounds of structure (XIV), wherein R_(e), R_(f), R₃₅,R₃₆, R₃₇, R₃₈, D₁ and p are as defined herein, a carbonyl group isrepresentative of the A group, as defined herein, oxygen isrepresentative of G₄, as defined herein, and a nitrate containingsubstituent is representative of the R₃₄ group, as defined herein, maybe prepared according to FIG. 42. Deprotection of the hydroxyl moiety ofthe compound of structure 54 (fluoride ion is the preferred method forremoving silyl ether protecting groups) followed by activation andnucleophilic displacement of the hydroxyl by a halogen affords thecompound of structure 57, wherein X is preferably a bromine or aniodine. Preferred methods for converting a hydroxyl group to a halogenmoiety are to first activate it as the mesylate or tosylate by reactingit with methansulfonyl chloride or p-toluesulfonyl chloride in an inertsolvent such as methylene chloride or THF in the presence of a base suchas triethylamine followed by nucleophilic displacement of the sulfonatemoiety with iodide or bromide by reaction with sodium iodide or sodiumbromide in refluxing acetone. Reaction of the compound of structure 57with a suitable nitrating agent such as silver nitrate in an inertsolvent such as acetonitrile affords the compound of structure XIVC.

[0363] Nitroso compounds of structure (XV), wherein R_(e), R_(f), R₃₇,R₃₈, D₁ and p are as defined herein, and a nitrite containing estersubstituent is representative of the R₂₅ group, as defined herein, maybe prepared according to FIG. 43. 1,2,3,4-Tetrahydrobeta-carboline ofthe formula 58 is converted to the N-acylated compound of the formula59, wherein P¹ is as defined herein, and oxygen is representative of G₄,as defined herein, by reaction with a hydroxy protected carboxylic estersubstituted cinnamic acid derivative. Preferred methods for theformation of amides are reacting the amine with the preformed acidchloride or symmetrical anhydride of the carboxylic acid or condensingthe amine and carboxylic acid with a dehydrating agent, such as DCC orEDAC.HCl, in the presence of a catalyst, such as DMAP or HOBt. Preferredprotecting groups for the alcohol moiety are silyl ethers, such as atrimethylsilyl or a tert-butyldimethylsilyl ether. Deprotection of thehydroxyl moiety (fluoride ion is the preferred method for removing silylether protecting groups) followed by reaction with a stoichometricquantity of a suitable nitrosylating agent, such as thionyl chloridenitrite, thionyl dinitrite, or nitrosonium tetrafluoroborate, in asuitable anhydrous solvent, such as dichloromethane, THF, DMF, oracetonitrile, with or without an amine base, such as pyridine ortriethylamine, affords the compound of structure XVA.

[0364] Nitroso compounds of structure (XV), wherein R_(e), R_(f), R₃₇,R₃₈, D₁ and p are as defined herein, and a nitrosothiol containing estersubstituent is representative of the R₂₅ group, as defined herein, maybe prepared according to FIG. 44. 1,2,3,4-Tetrahydrobeta-carboline ofthe formula 58 is converted to the N-acylated compound of the formula60, wherein P² is as defined herein, and oxygen is representative of G₄,as defined herein, by reaction with a sulfanyl protected carboxylicester substituted cinnamic acid derivative. Preferred methods for theformation of amides are reacting the amine with the preformed acidchloride or symmetrical anhydride of the carboxylic acid or condensingthe amine and carboxylic acid with a dehydrating agent, such as DCC orEDAC.HCl, in the presence of a catalyst, such as DMAP or HOBt. Preferredprotecting groups for the thiol moiety are as a thioester such as athioacetate or thiobenzoate, as a disulfide, as a thiocarbamate such asN-methoxymethyl thiocarbamate, or as a thioether such as aparamethoxy-benzyl thioether, a tetrahydropyranyl thioether or a2,4,6-trimethoxybenzyl thioether. Deprotection of the sulfanyl moiety(zinc in dilute aqueous acid, triphenylphosphine in water and sodiumborohydride are preferred methods for reducing disulfide groups whileaqueous base is typically utilized to hydrolyze thioesters andN-methoxymethyl thiocarbamates and mercuric trifluoroacetate, silvernitrate, or strong acids such as trifluoroacetic or hydrochloric acidand heat are used to remove a paramethoxybenzyl thioether, atetrahydropyranyl thioether, or a 2,4,6-trimethoxybenzyl thioethergroup) followed by reaction with a stoichometric quantity of a suitablenitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite,a lower alkyl nitrite such as tert-butyl nitrite, or nitrosoniumtetrafluoroborate in a suitable anhydrous solvent such as methylenechloride, THF, DMF, or acetonitrile with or without an amine base suchas pyridine or triethylamine affords the compound of structure XVB.Alternatively, treatment of the deprotected thiol derived from compound60 with a stoichiometric quantity of sodium nitrite in an acidic aqueousor alcoholic solution affords the compound of structure XVB.

[0365] Nitro compounds of structure (XV), wherein R_(e), R_(f), R₃₇,R₃₈, D₁ and p are as defined herein, and a nitrate containing estersubstituent is representative of the R₂₅ group, as defined herein, maybe prepared according to FIG. 45. 1,2,3,4-Tetrahydrobeta-carboline ofthe formula 58 is converted to the N-acylated compound of the formula61, wherein X is as defined herein, and oxygen is representative of G₄,as defined herein, by reaction with a halogen containing carboxylicester substituted cinnamic acid derivative. Preferred methods for theformation of amides are reacting the amine with the preformed acidchloride or symmetrical anhydride of the halide containing acid orcondensing the amine and halide containing acid with a dehydratingagent, such as DCC or EDAC.HCl in the presence of a catalyst, such asDMAP or HOBt. Preferred halides are bromide and iodide. Reaction of theamide of structure 61 with a suitable nitrating agent, such as silvernitrate in an inert solvent, such as acetonitrile, affords the compoundof structure XVC.

[0366] Nitroso compounds of structure (XVI), wherein R_(e), R_(f), R₄₀,R₄₁ and p are as defined herein, and a nitrite containing benzoic estersubstituent is representative of the R₄₂ group, as defined herein, maybe prepared according to FIG. 46. 2-Pyrazolin-5-one of the formula 62 isconverted to the ester of the formula 63, wherein P¹ is as definedherein, by reaction with a monoprotected diol. Preferred methods for theformation of esters are reacting the alcohol with the preformed acidchloride or symmetrical anhydride of the carboxylic acid or condensingthe alcohol and carboxylic acid with a dehydrating agent, such as DCC orEDAC.HCl, in the presence of a catalyst, such as DMAP or HOBt. Preferredprotecting groups for the alcohol moiety are silyl ethers, such as atrimethylsilyl or a tert-butyldimethylsilyl ether. Deprotection of thehydroxyl moiety (fluoride ion is the preferred method for removing silylether protecting groups) followed by reaction with a stoichometricquantity of a suitable nitrosylating agent, such as thionyl chloridenitrite, thionyl dinitrite, or nitrosonium tetrafluoroborate, in asuitable anhydrous solvent, such as dichloromethane, THF, DMF, oracetonitrile, with or without an amine base, such as pyridine ortriethylamine, affords the compound of structure XVIA.

[0367] Nitroso compounds of structure (XVI), wherein R_(e), R_(f), R₄₀,R₄₁ and p are as defined herein, and a nitrosothiol containing benzoicester substituent is representative of the R₄₂ group, as defined herein,may be prepared according to FIG. 47. 2-Pyrazolin-5-one of the formula62 is converted to the ester of the formula 64, wherein P² is as definedherein, by reaction with a sulfanyl protected alcohol. Preferred methodsfor the formation of esters are reacting the alcohol with the preformedacid chloride or symmetrical anhydride of the carboxylic acid orcondensing the alcohol and carboxylic acid with a dehydrating agent,such as DCC or EDAC.HCl, in the presence of a catalyst, such as DMAP orHOBt. Preferred protecting groups for the thiol moiety are as athioester such as a thioacetate or thiobenzoate, as a disulfide, as athiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioethersuch as a paramethoxy-benzyl thioether, a tetrahydropyranyl thioether ora 2,4,6-trimethoxybenzyl thioether. Deprotection of the sulfanyl moiety(zinc in dilute aqueous acid, triphenylphosphine in water and sodiumborohydride are preferred methods for reducing disulfide groups whileaqueous base is typically utilized to hydrolyze thioesters andN-methoxymethyl thiocarbamates and mercuric trifluoroacetate, silvernitrate, or strong acids such as trifluoroacetic or hydrochloric acidand heat are used to remove a paramethoxybenzyl thioether, atetrahydropyranyl thioether, or a 2,4,6-trimethoxybenzyl thioethergroup) followed by reaction with a stoichometric quantity of a suitablenitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite,a lower alkyl nitrite such as tert-butyl nitrite, or nitrosoniumtetrafluoroborate in a suitable anhydrous solvent such as methylenechloride, THF, DMF, or acetonitrile with or without an amine base suchas pyridine or triethylamine affords the compound of structure XVIB.Alternatively, treatment of the deprotected thiol derived from compound64 with a stoichiometric quantity of sodium nitrite in an acidic aqueousor alcoholic solution affords the compound of structure XVIB.

[0368] Nitro compounds of structure (XVI), wherein R_(e), R_(f), R₄₀,R₄₁ and p are as defined herein, and a nitrate containing benzoic estersubstituent is representative of the R₄₂ group, as defined herein, maybe prepared according to FIG. 48. 2-Pyrazolin-5-one of the formula 62 isconverted to the ester of the formula 65, wherein X is as definedherein, by reaction with a halogen containing alcohol. Preferred methodsfor the formation of esters are reacting the alcohol with the preformedacid chloride or symmetrical anhydride of the carboxylic acid orcondensing the alcohol and carboxylic acid with a dehydrating agent,such as DCC or EDAC.HCl, in the presence of a catalyst, such as DMAP orHOBt. Preferred halides are bromide and iodide. Reaction of the amide ofstructure 64 with a suitable nitrating agent, such as silver nitrate inan inert solvent, such as acetonitrile, affords the compound ofstructure XVIC.

[0369] Nitroso compounds of structure (XVII), wherein R_(e), R_(f), R₈,R₂₃, J and p are as defined herein, and a nitrite containing aminocontaining substituent is representative of the R₂₄ group, as definedherein, may be prepared according to FIG. 49. Chlorophthalazine of theformula 66 is converted to the compound of structure 67 by reaction withan amine containing a protected hydroxyl group, wherein P¹ is as definedherein. Preferred conditions for the formation of the compound ofstructure 67 are to heat the amine and the compound of structure 65 at170° C. for several hours in a high boiling inert solvent such as2-methylpyrrolidone in the presence of an amine base such asdiisopropylethylamine. Preferred protecting groups for the alcoholmoiety are silyl ethers, such as a trimethylsilyl or atert-butyldimethylsilyl ether. Deprotection of the hydroxyl moiety(fluoride ion is the preferred method for removing silyl etherprotecting groups) followed by reaction with a stoichometric quantity ofa suitable nitrosylating agent, such as thionyl chloride nitrite,thionyl dinitrite, or nitrosonium tetrafluoroborate, in a suitableanhydrous solvent, such as dichloromethane, THF, DMF, or acetonitrile,with or without an amine base, such as pyridine or triethylamine,affords the compound of structure XVIIA.

[0370] Nitroso compounds of structure (XVII), wherein R_(e), R_(f), R₈,R₂₃, J and p are as defined herein, and a nitrosothiol containing aminocontaining substituent is representative of the R₂₄ group, as definedherein, may be prepared according to FIG. 50. Chlorophthalazine of theformula 66 is converted to the compound of structure 68 by reaction withan amine containing a protected thiol group, wherein P² is as definedherein. Preferred conditions for the formation of the compound ofstructure 68 are to heat the amine and the compound of structure 65 at170° C. for several hours in a high boiling inert solvent such as2-methylpyrrolidone in the presence of an amine base such asdiisopropylethylamine. Preferred protecting groups for the thiol moietyare as a thioester such as a thioacetate or thiobenzoate, as adisulfide, as a thiocarbamate such as N-methoxymethyl thiocarbamate, oras a thioether such as a paramethoxy-benzyl thioether, atetrahydropyranyl thioether or a 2,4,6-trimethoxybenzyl thioether.Deprotection of the sulfanyl moiety (zinc in dilute aqueous acid,triphenylphosphine in water and sodium borohydride are preferred methodsfor reducing disulfide groups while aqueous base is typically utilizedto hydrolyze thioesters and N-methoxymethyl thiocarbamates and mercurictrifluoroacetate, silver nitrate, or strong acids such astrifluoroacetic or hydrochloric acid and heat are used to remove aparamethoxybenzyl thioether, a tetrahydropyranyl thioether, or a2,4,6-trimethoxybenzyl thioether group) followed by reaction with astoichometric quantity of a suitable nitrosylating agent such as thionylchloride nitrite, thionyl dinitrite, a lower alkyl nitrite such astert-butyl nitrite, or nitrosonium tetrafluoroborate in a suitableanhydrous solvent such as methylene chloride, THF, DMF, or acetonitrilewith or without an amine base such as pyridine or triethylamine affordsthe compound of structure XVIIB. Alternatively, treatment of thedeprotected thiol derived from compound 68 with a stoichiometricquantity of sodium nitrite in an acidic aqueous or alcoholic solutionaffords the compound of structure XVIIB.

[0371] Nitro compounds of structure (XVII), wherein R_(e), R_(f), R₈,R₂₃, J and p are as defined herein, and a nitrate containing substituentis representative of the R₂₄ group, as defined herein, may be preparedaccording to FIG. 51. Deprotection of the hydroxyl moiety of thecompound of structure 67 (fluoride ion is the preferred method forremoving silyl ether protecting groups) followed by activation andnucleophilic displacement of the hydroxyl by a halogen affords thecompound of structure 69, wherein X is preferably a bromine or aniodine. Preferred methods for converting a hydroxyl group to a halogenmoiety are to first activate it as the mesylate or tosylate by reactingit with methansulfonyl chloride or p-toluesulfonyl chloride in an inertsolvent such as methylene chloride or THF in the presence of a base suchas triethylamine followed by nucleophilic displacement of the sulfonatemoiety with iodide or bromide by reaction with sodium iodide or sodiumbromide in refluxing acetone. Reaction of the compound of structure 69with a suitable nitrating agent such as silver nitrate in an inertsolvent such as acetonitrile affords the compound of structure XVIIC.

[0372] Nitroso compounds of structure (XVIII), wherein R_(e), R_(f), R₈,R₂₆, R₂₇, R₂₈, R₂₉, R₄₄ and p are as defined herein, and a nitritecontaining ester substituted benzoate is representative of the D group,as defined herein, may be prepared according to FIG. 52. Anthranilicamide of the formula 70 is converted to the N-acylated compound of theformula 71, wherein P¹ is as defined herein, by reaction with a hydroxyprotected carboxylic ester substituted benzoic acid derivative.Preferred methods for the formation of amides are reacting the aminewith the preformed acid chloride or symmetrical anhydride of thecarboxylic acid or condensing the amine and carboxylic acid with adehydrating agent, such as DCC or EDAC.HCl, in the presence of acatalyst, such as DMAP or HOBt. Preferred protecting groups for thealcohol moiety are silyl ethers, such as a trimethylsilyl or atert-butyldimethylsilyl ether. Deprotection of the hydroxyl moiety(fluoride ion is the preferred method for removing silyl etherprotecting groups) followed by reaction with a stoichometric quantity ofa suitable nitrosylating agent, such as thionyl chloride nitrite,thionyl dinitrite, or nitrosonium tetrafluoroborate, in a suitableanhydrous solvent, such as dichloromethane, THF, DMF, or acetonitrile,with or without an amine base, such as pyridine or triethylamine,affords the compound of structure XVIIIA.

[0373] Nitroso compounds of structure (XVIII), wherein R_(e), R_(f), R₈,R₂₆, R₂₇, R₂₈, R₂₉, R₄₄ and p are as defined herein, and a nitrosothiolcontaining ester substituted benzoate is representative of the D group,as defined herein, may be prepared according to FIG. 53. Anthranilicamide of the formula 70 is converted to the N-acylated compound ofstructure 72, wherein P² is as defined herein, by reaction with asulfanyl protected carboxylic ester substituted benzoic acid derivative.Preferred methods for the formation of amides are reacting the aminewith the preformed acid chloride or symmetrical anhydride of thecarboxylic acid or condensing the amine and carboxylic acid with adehydrating agent, such as DCC or EDAC.HCl, in the presence of acatalyst, such as DMAP or HOBt. Preferred protecting groups for thethiol moiety are as a thioester such as a thioacetate or thiobenzoate,as a disulfide, as a thiocarbamate such as N-methoxymethylthiocarbamate, or as a thioether such as a paramethoxy-benzyl thioether,a tetrahydropyranyl thioether or a 2,4,6-trimethoxybenzyl thioether.Deprotection of the sulfanyl moiety (zinc in dilute aqueous acid,triphenylphosphine in water and sodium borohydride are preferred methodsfor reducing disulfide groups while aqueous base is typically utilizedto hydrolyze thioesters and N-methoxymethyl thiocarbamates and mercurictrifluoroacetate, silver nitrate, or strong acids such astrifluoroacetic or hydrochloric acid and heat are used to remove aparamethoxybenzyl thioether, a tetrahydropyranyl thioether, or a2,4,6-trimethoxybenzyl thioether group) followed by reaction with astoichometric quantity of a suitable nitrosylating agent such as thionylchloride nitrite, thionyl dinitrite, a lower alkyl nitrite such astert-butyl nitrite, or nitrosonium tetrafluoroborate in a suitableanhydrous solvent such as methylene chloride, THF, DMF, or acetonitrilewith or without an amine base such as pyridine or triethylamine affordsthe compound of structure XVIIIB. Alternatively, treatment of thedeprotected thiol derived from compound 72 with a stoichiometricquantity of sodium nitrite in an acidic aqueous or alcoholic solutionaffords the compound of structure XVIIIB.

[0374] Nitro compounds of structure (XVIII), wherein R_(e), R_(f), R₈,R₂₆, R₂₇, R₂₈, R₂₉, R₄₄ and p are as defined herein, and a nitratecontaining ester substituted benzoate is representative of the D group,as defined herein, may be prepared according to FIG. 54. Anthranilicamide of the formula 70 is converted to the N-acylated compound of theformula 73, wherein X is as defined herein, by reaction with a halogencontaining carboxylic ester substituted benzoic acid derivative.Preferred methods for the formation of amides are reacting the aminewith the preformed acid chloride or symmetrical anhydride of the halidecontaining acid or condensing the amine and halide containing acidderivative with a dehydrating agent, such as DCC or EDAC.HCl in thepresence of a catalyst, such as DMAP or HOBt. Preferred halides arebromide and iodide. Reaction of the amide of structure 73 with asuitable nitrating agent, such as silver nitrate in an inert solvent,such as acetonitrile, affords the compound of structure XVIIIC.

[0375] Nitroso compounds of structure (XIX), wherein R_(e), R_(f), R₈,G₄, T and p are as defined herein, and nitrite containing substituentsare representative of the R₄₆ and R₄₇ groups, as defined herein, may beprepared according to FIG. 55. Chloroquinazoline of the formula 74 isconverted to the compound of structure 75 by reaction with ansubstituted benzyl amine containing protected hydroxyl groups, whereinP¹ is as defined herein. Preferred conditions for the formation of thecompound of structure 75 are to heat the amine and the compound ofstructure 74 at an elevated temperature for several hours in an inertsolvent such as isopropanol at reflux. Compound of the formula 75 isthen converted into compound of the formula 76 by reduction of the nitrosubstituent followed by reaction with phosgene, thiophosgene or anequivalent in the presence of a base such as pyridine or triethylamine.Preferred methods for the reduction of nitro groups are to use hydrogen(1-3 atmospheres) in the presence of a palladium catalyst such aspalladium on charcoal in an inert solvent such as ethanol at atemperature of 25° C. to 50° C. or iron, tin or zinc metal in aqueous oralcoholic acid. Preferred protecting groups for the alcohol moieties aresilyl ethers, such as trimethylsilyl or tert-butyldimethylsilyl ethers.Deprotection of the hydroxyl moieties (fluoride ion is the preferredmethod for removing silyl ether protecting groups) followed by reactionwith a stoichometric quantity of a suitable nitrosylating agent, such asthionyl chloride nitrite, thionyl dinitrite, or nitrosoniumtetrafluoroborate, in a suitable anhydrous solvent, such asdichloromethane, THF, DMF, or acetonitrile, with or without an aminebase, such as pyridine or triethylamine, affords the compound ofstructure XIXA.

[0376] Nitroso compounds of structure (XIX), wherein R_(e), R_(f), R₈,G₄, T and p are as defined herein, and nitrosothiol containingsubstituents are representative of the R₄₆ and R₄₇ groups, as definedherein, may be prepared according to FIG. 56. Chloroquinazoline of theformula 74 is converted to the compound of structure 77 by reaction witha substituted benzyl amine containing protected thiol groups, wherein P²is as defined herein. Preferred conditions for the formation of thecompound of structure 77 are to heat the amine and the compound ofstructure 74 for several hours in an inert solvent such as isopropanolat reflux. Compound of the formula 77 is then converted into compound ofthe formula 78 by reduction of the nitro substituent followed byreaction with phosgene, thiophosgene or an equivalent in the presence ofa base such as pyridine or triethylamine. Preferred methods for thereduction of nitro groups are to use hydrogen (1-3 atmospheres) in thepresence of a palladium catalyst such as palladium on charcoal in aninert solvent such as ethanol at a temperature of 25° C. to 50° C. oriron, tin or zinc metal in aqueous or alcoholic acid. Preferredprotecting groups for the thiol moiety are as a thioester such as athioacetate or thiobenzoate, as a disulfide, as a thiocarbamate such asN-methoxymethyl thiocarbamate, or as a thioether such as aparamethoxy-benzyl thioether, a tetrahydropyranyl thioether or a2,4,6-trimethoxybenzyl thioether. Deprotection of the sulfanyl moiety(zinc in dilute aqueous acid, triphenylphosphine in water and sodiumborohydride are preferred methods for reducing disulfide groups whileaqueous base is typically utilized to hydrolyze thioesters andN-methoxymethyl thiocarbamates and mercuric trifluoroacetate, silvernitrate, or strong acids such as trifluoroacetic or hydrochloric acidand heat are used to remove a paramethoxybenzyl thioether, atetrahydropyranyl thioether, or a 2,4,6-trimethoxybenzyl thioethergroup) followed by reaction with a stoichometric quantity of a suitablenitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite,a lower alkyl nitrite such as tert-butyl nitrite, or nitrosoniumtetrafluoroborate in a suitable anhydrous solvent such as methylenechloride, THF, DMF, or acetonitrile with or without an amine base suchas pyridine or triethylamine affords the compound of structure XIXB.Alternatively, treatment of the deprotected thiol derived from compound78 with a stoichiometric quantity of sodium nitrite in an acidic aqueousor alcoholic solution affords the compound of structure XIXB.

[0377] Nitro compounds of structure (XIX), wherein R_(e), R_(f), R₈, G₄,T, k and p are as defined herein, and nitrate containing substituentsare representative of the R₄₆ and R₄₇ groups, as defined herein, may beprepared according to FIG. 57. Deprotection of the hydroxyl moiety ofthe compound of structure 76 (fluoride ion is the preferred method forremoving silyl ether protecting groups) followed by activation andnucleophilic displacement of the hydroxyl by a halogen affords thecompound of structure 79, wherein X is preferably a bromine or aniodine. Preferred methods for converting a hydroxyl group to a halogenmoiety are to first activate it as the mesylate or tosylate by reactingit with methansulfonyl chloride or p-toluesulfonyl chloride in an inertsolvent such as methylene chloride or THF in the presence of a base suchas triethylamine followed by nucleophilic displacement of the sulfonatemoiety with iodide or bromide by reaction with sodium iodide or sodiumbromide in refluxing acetone. Reaction of the compound of structure 79with a suitable nitrating agent such as silver nitrate in an inertsolvent such as acetonitrile affords the compound of structure XIXC.

[0378] The compounds of the present invention include PDE inhibitors,including those described herein, which have been nitrosated and/ornitrosylated through one or more sites such as oxygen (hydroxylcondensation), sulfur (sulflhydryl condensation), carbon and/ornitrogen. The nitrosated and/or nitrosylated PDE inhibitors of thepresent invention donate, transfer or release a biologically active formof nitrogen monoxide (nitric oxide).

[0379] Nitrogen monoxide can exist in three forms: NO— (nitroxyl), NO.(nitric oxide) and NO⁺ (nitrosonium). NO. is a highly reactiveshort-lived species that is potentially toxic to cells. This is criticalbecause the pharmacological efficacy of NO depends upon the form inwhich it is delivered. In contrast to the nitric oxide radical (NO.),nitrosonium (NO⁺) does not react with O₂ or O₂— species, andfunctionalities capable of transferring and/or releasing NO⁺ and NO— arealso resistant to decomposition in the presence of many redox metals.Consequently, administration of charged NO equivalents (positive and/ornegative) does not result in the generation of toxic by-products or theelimination of the active NO moiety.

[0380] Compounds contemplated for use in the present invention (e.g.,PDE inhibitors antagonists and/or nitrosated and/or nitrosylated PDEinhibitors) are, optionally, used in combination with nitric oxide andcompounds that release nitric oxide or otherwise directly or indirectlydeliver or transfer nitric oxide to a site of its activity, such as on acell membrane in vivo.

[0381] The term “nitric oxide” encompasses uncharged nitric oxide (NO.)and charged nitrogen monoxide species, preferably charged nitrogenmonoxide species, such as nitrosonium ion (NO⁺) and nitroxyl ion (NO—).The reactive form of nitric oxide can be provided by gaseous nitricoxide. The nitric oxide releasing, delivering or transferring compounds,have the structure F—NO, wherein F is a nitric oxide releasing,delivering or transferring moiety, include any and all such compoundswhich provide nitric oxide to its intended site of action in a formactive for its intended purpose. The term “NO adducts” encompasses anynitric oxide releasing, delivering or transferring compounds, including,for example, S-nitrosothiols, organic nitrites, organic nitrates,S-nitrothiols, sydnonimines, 2-hydroxy-2-nitrosohydrazines (NONOates),(E)-alkyl-2-[(E)-hydroxyimino]-5-nitro-3-hexene amines or amides,nitrosoamines, furoxanes as well as substrates for the endogenousenzymes which synthesize nitric oxide. The “NO adducts” can bemono-nitrosylated, poly-nitrosylated, mono-nitrosated and/orpoly-nitrosated at a variety of naturally susceptible or artificiallyprovided binding sites for nitric oxide.

[0382] One group of NO adducts is the S-nitrosothiols, which arecompounds that include at least one —S—NO group. These compounds includeS-nitroso-polypeptides (the term “polypeptide” includes proteins andpolyamino acids that do not possess an ascertained biological function,and derivatives thereof); S-nitrosylated amino acids (including naturaland synthetic amino acids and their stereoisomers and racemic mixturesand derivatives thereof); S-nitrosylated sugars; S-nitrosylated,modified and unmodified, oligonucleotides (preferably of at least 5, andmore preferably 5-200 nucleotides); straight or branched, saturated orunsaturated, aliphatic or aromatic, substituted or unsubstitutedS-nitrosylated hydrocarbons; and S-nitroso heterocyclic compounds.S-nitrosothiols and methods for preparing them are described in U.S.Pat. Nos. 5,380,758 and 5,703,073; WO 97/27749; WO 98/19672; and Oae etal, Org. Prep. Proc. Int., 15(3):165-198 (1983), the disclosures of eachof which are incorporated by reference herein in their entirety.

[0383] Another embodiment of the present invention is S-nitroso aminoacids where the nitroso group is linked to a sulfur group of asulfur-containing amino acid or derivative thereof. Such compoundsinclude, for example, S-nitroso-N-acetylcysteine, S-nitroso-captopril,S-nitroso-N-acetylpenicillamine, S-nitroso-homocysteine,S-nitroso-cysteine and S-nitroso-glutathione.

[0384] Suitable S-nitrosylated proteins include thiol-containingproteins (where the NO group is attached to one or more sulfur groups onan amino acid or amino acid derivative thereof) from various functionalclasses including enzymes, such as tissue-type plasminogen activator(TPA) and cathepsin B; transport proteins, such as lipoproteins; hemeproteins, such as hemoglobin and serum albumin; and biologicallyprotective proteins, such as immunoglobulins and cytokines. Suchnitrosylated proteins are described in WO 93/09806, the disclosure ofwhich is incorporated by reference herein in its entirety. Examplesinclude polynitrosylated albumin where one or more thiol or othernucleophilic centers in the protein are modified.

[0385] Other examples of suitable S-nitrosothiols include:

[0386] (i) HS[C(R_(e))(R_(f))]_(m)SNO;

[0387] (ii) ONS[C(R_(e))(R_(f))]_(m)R_(e); and

[0388] (iii) H₂N—CH(CO₂H)—(CH₂)_(m)—C(O)NH—CH(CH₂SNO)—C(O)NH—CH₂—CO₂H;

[0389] wherein m is an integer of from 2 to 20; R_(e) and R_(f) are eachindependently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy,an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl,a cycloalkylalkyl, a heterocyclicalkyl, am alkoxy, a haloalkoxy, anamino, an alkylamino, a dialkylamino, an arylamino, a diarylamino, analkylarylamino an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, analkylsulfonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio,an arylthio, a cyano, an aminoalkyl, an aminoaryl, an alkoxy, an aryl,an arylalkyl, an alkylaryl, a carboxamido, a alkyl carboxamido, an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylicacid, an arylcarboxylic acid, an ester, a carboxylic ester, analkylcarboxylic ester, an arylcarboxylic ester, a haloalkoxy, asulfonamido, an alkylsulfonamido, an arylsulfonamido, a urea, a nitro,or -T-Q; or R_(e) and R_(f) taken together are a carbonyl, amethanthial, a heterocyclic ring, a cycloalkyl group or a bridgedcycloalkyl group; Q is —NO or —NO₂; and T is independently a covalentbond, an oxygen, S(O)_(o) or NR_(i), wherein o is an integer from 0 to2, and R_(i) is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid,an aryl carboxylic acid, an alkylcarboxylic ester, an arylcarboxylicester, an alkylcarboxamido, an arylcarboxamido, an alkylaryl, analkylsulfinyl, an alkylsulfonyl, an arylsulfinyl, an arylsulfonyl, asulfonamido, carboxamido, —CH₂—C(T-Q)(R_(e))(R_(f)), or —(N₂O₂—)M⁺,wherein M⁺ in an organic or inorganic cation; with the proviso that whenR_(i) is —CH₂—C(T-Q)(R_(e))(R_(f)) or —(N₂O₂—)M⁺; then “-T-Q” can be ahydrogen, an alkyl group, an alkoxyalkyl group, an aminoalkyl group, ahydroxy group or an aryl group.

[0390] In cases where R_(e) and R_(f) are a heterocyclic ring or takentogether R_(e) and R_(f) are a heterocyclic ring, then R_(i) can be asubstituent on any disubstituted nitrogen contained within the radicalwherein R_(i) is as defined herein.

[0391] Nitrosothiols can be prepared by various methods of synthesis. Ingeneral, the thiol precursor is prepared first, then converted to theS-nitrosothiol derivative by nitrosation of the thiol group with NaNO₂under acidic conditions (pH is about 2.5) which yields the S-nitrosoderivative. Acids which can be used for this purpose include aqueoussulfuric, acetic and hydrochloric acids. The thiol precursor can also benitrosylated by reaction with an organic nitrite such as tert-butylnitrite, or a nitrosonium salt such as nitrosonium tetraflurorborate inan inert solvent.

[0392] Another group of NO adducts for use in the present invention,where the NO adduct is a compound that donates, transfers or releasesnitric oxide, include compounds comprising at least one ON—O—, ON—N— orON—C— group. The compounds that include at least one ON—O—, ON—N— orON—C— group are preferably ON—O—, ON—N— or ON—C-polypeptides (the term“polypeptide” includes proteins and polyamino acids that do not possessan ascertained biological function, and derivatives thereof); ON—O—,ON—N— or ON—C-amino acids (including natural and synthetic amino acidsand their stereoisomers and racemic mixtures); ON—O—, ON—N— orON—C-sugars; ON—O—, ON—N— or ON—C— modified or unmodifiedoligonucleotides (comprising at least 5 nucleotides, preferably 5-200nucleotides); ON—O—, ON—N— or ON—C— straight or branched, saturated orunsaturated, aliphatic or aromatic, substituted or unsubstitutedhydrocarbons; and ON—O—, ON—N— or ON—C-heterocyclic compounds.

[0393] Another group of NO adducts for use in the present inventioninclude nitrates that donate, transfer or release nitric oxide, such ascompounds comprising at least one O₂N—O—, O₂N—N—, O₂N—S— or O₂N—C—group. Preferred among these compounds are O₂N—O—, O₂N—N—, O₂N—S— orO₂N—C— polypeptides (the term “polypeptide” includes proteins and alsopolyamino acids that do not possess an ascertained biological function,and derivatives thereof); O₂N—O—, O₂N—N—, O₂N—S— or O₂N—C— amino acids(including natural and synthetic amino acids and their stereoisomers andracemic mixtures); O₂N—O—, O₂N—N—, O₂N—S— or O₂N—C-sugars; O₂N—O—,O₂N—N—, O₂N—S— or O₂N—C— modified and unmodified oligonucleotides(comprising at least 5 nucleotides, preferably 5-200 nucleotides);O₂N—O—, O₂N—N—, O₂N—S— or O₂N—C— straight or branched, saturated orunsaturated, aliphatic or aromatic, substituted or unsubstitutedhydrocarbons; and O₂N—O—, O₂N—N—, O₂N—S— or O₂N—C— heterocycliccompounds. Preferred examples of compounds comprising at least oneO₂N—O—, O₂N—N—, O₂N—S— or O₂N—C— group include isosorbide dinitrate,isosorbide mononitrate, clonitrate, erythrityltetranitrate, mannitolhexanitrate, nitroglycerin, pentaerythritoltetranitrate, pentrinitroland propatylnitrate.

[0394] Another group of NO adducts are N-oxo-N-nitrosoamines thatdonate, transfer or release nitric oxide and are represented by theformula: R¹R²N—N(O-M⁺)—NO, where R¹ and R² are each independently apolypeptide, an amino acid, a sugar, a modified or unmodifiedoligonucleotide, a straight or branched, saturated or unsaturated,aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or aheterocyclic group, and where M⁺ is an organic or inorganic cation, suchas, for example, an alkyl substituted ammonium cation or a Group I metalcation.

[0395] Another group of NO adducts are thionitrates that donate,transfer or release nitric oxide and are represented by the formula:R¹—(S)—NO₂, where R¹ is a polypeptide, an amino acid, a sugar, amodified or unmodified oligonucleotide, a straight or branched,saturated or unsaturated, aliphatic or aromatic, substituted orunsubstituted hydrocarbon, or a heterocyclic group. Preferred are thosecompounds where R¹ is a polypeptide or hydrocarbon with a pair or pairsof thiols that are sufficiently structurally proximate, i.e., vicinal,that the pair of thiols will be reduced to a disulfide. Compounds whichform disulfide species release nitroxyl ion (NO—) and uncharged nitricoxide (NO.). Compounds where the thiol groups are not sufficiently closeto form disulfide bridges generally provide nitric oxide as the NO— formand not as the uncharged NO. form.

[0396] The present invention is also directed to agents that stimulateendogenous NO or elevate levels of endogenous endothelium-derivedrelaxing factor (EDRF) in vivo or are substrates for nitric oxidesynthase. Such compounds include, for example, L-arginine,L-homoarginine, and N-hydroxy-L-arginine, including their nitrosated andnitrosylated analogs (e.g., nitrosated L-arginine, nitrosylatedL-arginine, nitrosated N-hydroxy-L-arginine, nitrosylatedN-hydroxy-L-arginine, nitrosated L-homoarginine and nitrosylatedL-homoarginine), precursors of L-arginine and/or physiologicallyacceptable salts thereof, including, for example, citrulline, omithineor glutamine, inhibitors of the enzyme arginase (e.g.,N-hydroxy-L-arginine and 2(S)-amino-6-boronohexanoic acid) and thesubstrates for nitric oxide synthase, cytokines, adenosin, bradykinin,calreticulin, bisacodyl, and phenolphthalein. EDRF is a vascularrelaxing factor secreted by the endothelium, and has been identified asnitric oxide (NO) or a closely related derivative thereof (Palmer et al,Nature, 327:524-526 (1987); Ignarro et al, Proc. Natl. Acad. Sci. USA,84:9265-9269 (1987)).

[0397] The present invention is also based on the discovery that theadministration of a therapeutically effective amount of the compoundsand compositions described herein is effective for treating orpreventing sexual dysfunctions or enhancing sexual responses inpatients, including males and females. For example, the patient can beadministered a therapeutically effective amount of at least onenitrosated and/or nitrosylated PDE inhibitor of the present invention.In another embodiment, the patient can be administered a therapeuticallyeffective amount of at least one PDE inhibitor, optionally substitutedwith at least one NO and/or NO₂ group, and at least one compound thatdonates, transfers or releases nitric oxide, or elevates levels ofendogenous EDRF or nitric oxide, or is a substrate for nitric oxidesynthase. In yet another embodiment, the patient can be administered atherapeutically effective amount of at least one PDE inhibitor,optionally substituted with at least one NO and/or NO₂ group, and atleast one vasoactive agent, and, optionally, at least one compound thatdonates, transfers or releases nitric oxide, or elevates levels ofendogenous EDRF or nitric oxide, or is a substrate for nitric oxidesynthase. The compounds can be administered separately or in the form ofa composition.

[0398] A vasoactive agent is any therapeutic agent capable of relaxingvascular smooth muscle. Suitable vasoactive agents include, but are notlimited to, potassium channel activators (such as, for example,nicorandil, pinacidil, cromakalim, minoxidil, aprilkalim, loprazolam andthe like); calcium blockers (such as, for example, nifedipine,veraparmil, diltiazem, gallopamil, niludipine, nimodipins, nicardipine,and the like); β-blockers (such as, for example, butixamine,dichloroisoproterenol, propanolol, alprenolol, bunolol, nadolol,oxprenolol, perbutolol, pinodolol, sotalol, timolol, metoprolol,atenolol, acebutolol, bevantolol, pafenolol, tolamodol, and the like);long and short acting α-adrenergic receptor antagonist (such as, forexample, phenoxybenzamide, dibenamine, doxazosin, terazosin,phentolamine, tolazoline, prozosin, trimazosin, yohimbine, moxisylyteand the like adenosine, ergot alkaloids (such as, for example,ergotamine, ergotamine analogs, including, for example, acetergamine,brazergoline, bromerguride, cianergoline, delorgotrile, disulergine,ergonovine maleate, ergotamine tartrate, etisulergine, lergotrile,lysergide, mesulergine, metergoline, metergotamine, nicergoline,pergolide, propisergide, proterguride, terguride); vasoactive intestinalpeptides (such as, for example, peptide histidine isoleucine, peptidehistidine methionine, substance P, calcitonin gene-related peptide,neurokinin A, bradykinin, neurokinin B, and the like); dopamine agonists(such as, for example, apomorphine, bromocriptine, testosterone,cocaine, strychnine, and the like); opioid antagonists (such as, forexample, naltrexone, and the like); prostaglandins (such as, forexample, alprostadil, prostaglandin E₂, prostaglandin F₂, misoprostol,enprostil, arbaprostil, unoprostone, trimoprostil, carboprost,limaprost, gemeprost, lantanoprost, ornoprostil, beraprost, sulpostrone,rioprostil, and the like); endothelin antagonists (such as, for example,bosentan, sulfonamide endothelin antagonists, BQ-123, SQ 28608, and thelike) and mixtures thereof.

[0399] Another embodiment of the present invention provides methods toprevent or treat diseases induced by the increased metabolism of cyclicguanosine 3′,5′-monophosphate (cGMP), including, for example,hypertension, pulmonary hypertension, congestive heart failure, renalfailure, myocardial infraction, stable, unstable and variant(Prinzmetal) angina, atherosclerosis, cardiac edema, renalinsufficiency, nephrotic edema, hepatic edema, stroke, asthma,bronchitis, chronic obstructive pulmonary disease (COPD), cysticfibrosis, dementia, immunodeficiency, premature labor, dysmenorrhoea,benign prostatic hyperplasis (BPH), bladder outlet obstruction,incontinence, conditions of reduced blood vessel patency, e.g.,postpercutaneous transluminal coronary angioplasty (post-PTCA),peripheral vascular disease, allergic rhinitis, glucoma and diseasescharacterized by disorders of gut motility, e.g, irritable bowelsyndrome (IBS) by administering to a patient in need thereof atherapeutically effective amount of the compounds and/or compositionsdescribed herein. For example, the patient can be administered atherapeutically effective amount of at least one nitrosated and/ornitrosylated PDE inhibitor of the present invention. In anotherembodiment, the patient can be administered a therapeutically effectiveamount of at least one PDE inhibitor, optionally substituted with atleast one NO and/or NO₂ group, and at least one compound that donates,transfers or releases nitric oxide, or elevates levels of endogenousEDRF or nitric oxide or is a substrate for nitric oxide synthase. In yetanother embodiment, the patient can be administered a therapeuticallyeffective amount of at least one PDE inhibitor, optionally substitutedwith at least one NO and/or NO₂ group, and at least one vasoactiveagent, and, optionally, at least one compound that donates, transfers orreleases nitric oxide, or elevates levels of endogenous EDRF or nitricoxide, or is a substrate for nitric oxide synthase. The compounds andcompositions of the present invention can also be administered incombination with other medications used for the treatment of thesedisorders.

[0400] When administered in vivo, the compounds and compositions of thepresent invention can be administered in combination withpharmaceutically acceptable carriers and in dosages described herein.When the compounds and compositions of the present invention areadministered as a mixture of at least one nitrosated and/or nitrosylatedPDE inhibitor or at least one PDE inhibitor and at least one nitricoxide donor, they can also be used in combination with one or moreadditional compounds which are known to be effective against thespecific disease state targeted for treatment (e.g., vasoactive agents).The nitric oxide donors and/or vasoactive agents can be administeredsimultaneously with, subsequently to, or prior to administration of thePDE inhibitors, including those that are substituted with one or more NOand/or NO₂ groups, and/or other additional compounds.

[0401] The compounds and compositions of the present invention can beadministered by any available and effective delivery system including,but not limited to, orally, bucally, parenterally, by inhalation spray,by topical application, by injection into the corpus cavernosum tissue,by transurethral drug delivery, transdermally, vaginally, or rectally(e.g., by the use of suppositories) in dosage unit formulationscontaining conventional nontoxic pharmaceutically acceptable carriers,adjuvants, and vehicles, as desired. Parenteral includes subcutaneousinjections, intravenous, intramuscular, intrasternal injection, orinfusion techniques. Transdermal drug administration, which is known toone skilled in the art, involves the delivery of pharmaceutical agentsvia percutaneous passage of the drug into the systemic circulation ofthe patient. Topical administration can also involve transdermal patchesor iontophoresis devices. Other components can be incorporated into thetransdermal patches as well. For example, compositions and/ortransdermal patches can be formulated with one or more preservatives orbacteriostatic agents including, but not limited to, methylhydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkoniumchloride, and the like.

[0402] Solid dosage forms for oral administration can include capsules,tablets, effervescent tablets, chewable tablets, pills, powders,sachets, granules and gels. In such solid dosage forms, the activecompounds can be admixed with at least one inert diluent such assucrose, lactose or starch. Such dosage forms can also comprise, as innormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, effervescent tablets, and pills, the dosage forms can alsocomprise buffering agents. Soft gelatin capsules can be prepared tocontain a mixture of the active compounds or compositions of the presentinvention and vegetable oil. Hard gelatin capsules can contain granulesof the active compound in combination with a solid, pulverulent carriersuch as lactose, saccharose, sorbitol, mannitol, potato starch, cornstarch, amylopectin, cellulose derivatives of gelatin. Tablets and pillscan be prepared with enteric coatings.

[0403] Liquid dosage forms for oral administration can includepharmaceutically acceptable emulsions, solutions, suspensions, syrups,and elixirs containing inert diluents commonly used in the art, such aswater. Such compositions can also comprise adjuvants, such as wettingagents, emulsifying and suspending agents, and sweetening, flavoring,and perfuming agents.

[0404] Dosage forms for topical administration of the compounds andcompositions of the present invention can include creams, sprays,lotions, gels, ointments, coatings for condoms and the like.Administration of the cream or gel can be accompanied by use of anapplicator or by transurethral drug delivery using a syringe with orwithout a needle or penile or vaginal insert or device, and is withinthe skill of the art. Typically a lubricant and/or a local anestheticfor desensitization can also be included in the formulation or providedfor use as needed. Lubricants include, for example, K—Y jelly (availablefrom Johnson & Johnson) or a lidocaine jelly, such as Xylocalne 2% jelly(available from Astra Pharmaceutical Products). Local anestheticsinclude, for example, novocaine, procaine, tetracaine, benzocaine andthe like. The compounds and compositions of the present invention willtypically be administered in a pharmaceutical composition containing oneor more selected carriers or excipients. Examples of suitable carriersinclude, for example, water, silicone, waxes, petroleum jelly,polyethylene glycol, propylene glycol, liposomes, sugars, and the like.The compositions can also include one or more permeation enhancersincluding, for example, dimethylsulfoxide (DMSO), dimethyl formamide(DMF), N,N-dimethylacetamide (DMA), decylmethylsulfoxide (C10MSO),polyethylene glycol monolaurate (PEGML), glyceral monolaurate, lecithin,1-substituted azacycloheptan-2-ones, particularly1-N-dodecylcyclazacylcoheptan-2-ones (available under the trademarkAzone™ from Nelson Research & Development Co., Irvine, Calif.), alcoholsand the like.

[0405] Suppositories for vaginal or rectal administration of thecompounds and compositions of the invention can be prepared by mixingthe compounds or compositions with a suitable nonirritating excipientsuch as cocoa butter and polyethylene glycols which are solid at roomtemperature but liquid at rectal temperature, such that they will meltin the rectum and release the drug.

[0406] Injectable preparations, for example, sterile injectable aqueousor oleaginous suspensions can be formulated according to the known artusing suitable dispersing agents, wetting agents and/or suspendingagents. The sterile injectable preparation can also be a sterileinjectable solution or suspension in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that can be used are water,Ringer's solution, and isotonic sodium chloride solution. Sterile fixedoils are also conventionally used as a solvent or suspending medium.

[0407] The compounds and compositions of the present invention can beformulated as pharmaceutically acceptable neutral or acid salt forms.Pharmaceutically acceptable salts include, for example, those formedwith free amino groups such as those derived from hydrochloric,hydrobromic, hydroiodide, phosphoric, sulfuric, acetic, citric, benzoic,fumaric, glutamic, lactic, malic, maleic, succinic, tartaric,p-toluenesulfonic, methanesulfonic acids, gluconic acid, and the like,and those formed with free carboxyl groups, such as those derived fromsodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine,triethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.

[0408] “Therapeutically effective amount” refers to the amount of thePDE inhibitor, nitrosated and/or nitrosylated PDE inhibitor, nitricoxide donor and/or vasoactive agent that is effective to achieve itsintended purpose. While individual patient needs may vary, determinationof optimal ranges for effective amounts of each of the compounds andcompositions is within the skill of the art. Generally, the dosagerequired to provide an effective amount of the composition, and whichcan be adjusted by one of ordinary skill in the art will vary, dependingon the age, health, physical condition, sex, weight, extent of thedysfunction of the recipient, frequency of treatment and the nature andscope of the dysfunction.

[0409] The amount of a given PDE inhibitor (including nitrosated and/ornitrosylated PDE inhibitors) which will be effective in the preventionor treatment of a particular dysfunction or condition will depend on thenature of the dysfunction or condition, and can be determined bystandard clinical techniques, including reference to Goodman and Gilman,supra; The Physician's Desk Reference, supra; Medical Economics Company,Inc., Oradell, N.J., 1995; and Drug Facts and Comparisons, Inc., St.Louis, Mo., 1993. The precise dose to be used in the formulation willalso depend on the route of administration, and the seriousness of thedysfunction or disorder, and should be decided by the physician and thepatient's circumstances.

[0410] The usual doses of PDE inhibitors (including nitrosated and/ornitrosylated PDE inhibitors) are about 0.001 mg to about 100 mg per day,preferably about 0.5 mg to about 50 mg per day. The oral dose of PDEinhibitors (including nitrosated and/or nitrosylated PDE inhibitors) areabout 1 mg to about 200 mg per day preferably about 5 mg to about 100 mgper day.

[0411] The doses of nitric oxide donors in the pharmaceuticalcomposition can be in amounts of about 0.001 mg to about 20 g and theactual amount administered will be dependent on the specific nitricoxide donor. For example, when L-arginine is the nitric oxide donor, thedose is about 2 g/day to about 6 g/day, preferably about 3 g/day,administered orally at least one hour prior to sexual activity or sexualintercourse. Effective doses can be extrapolated from dose-responsecurves derived from in vitro or animal model test systems and are in thesame ranges or less than as described for the commercially availablecompounds in the Physician's Desk Reference, supra.

[0412] The nitrosated and/or nitrosylated PDE inhibitors of theinvention are used at dose ranges and over a course of dose regimen andare administered in the same or substantially equivalentvehicles/carrier by the same or substantially equivalent as theirnon-nitrosated/nitrosylated counterparts. The nitrosated and/ornitrosylated compounds of the invention can also be used in lower dosesand in less extensive regimens of treatment. The amount of activeingredient that can be combined with the carrier materials to produce asingle dosage form will vary depending upon the host treated and theparticular mode of administration.

[0413] The dosage regimen for treating a condition with the compoundsand/or compositions of this invention is selected in accordance with avariety of factors, including the type, age, weight, sex, diet andmedical condition of the patient, the severity of the dysfunction, theroute of administration, pharmacological considerations such as theactivity, efficacy, pharmacokinetic and toxicology profiles of theparticular compound used, whether a drug delivery system is used, andwhether the compound is administered as part of a drug combination.Thus, the dosage regimen actually used can vary widely and therefore maydeviate from the preferred dosage regimen set forth herein.

[0414] Particularly preferred methods of administration of thecontemplated PDE inhibitor compositions (including nitrosated and/ornitrosylated PDE inhibitor compositions) for the treatment of malesexual dysfunction are by oral administration, by transdermalapplication, by injection into the corpus cavernosum, by transurethraladministration or by the use of suppositories. The preferred methods ofadministration for female sexual dysfunction are by oral administration,topical application, transdermal application or by the use ofsuppositories.

[0415] The present invention also provides pharmaceutical kitscomprising one or more containers filled with one or more of theingredients of the pharmaceutical compounds and/or compositions of thepresent invention, including, one or more PDE inhibitors, optionallysubstituted with one or more NO and/or NO₂ groups, one or more of the NOdonors, and one or more vasoactive agents. Such kits can also include,for example, other compounds and/or compositions (e.g., permeationenhancers, lubricants, and the like), a device(s) for administering thecompounds and/or compositions, and written instructions in a formprescribed by a governmental agency regulating the manufacture, use orsale of pharmaceuticals or biological products, which instructions canalso reflects approval by the agency of manufacture, use or sale forhuman administration.

EXAMPLES Example 1 2,6-bis(diethyl(3-methyl-3-(nitrosothio)butyric AcidEster)amino)-4,8-dipiperidinopyrimido-[5,4-d]-pyrimidine

[0416] 1a. 3-Methyl-3(2,4,6-trimethoxyphenylmethylthio)butyric Acid

[0417] To a solution of 3-mercapto-3-methylbutyric acid (Sweetman et al,J. Med. Chem., 14:868 (1971)) (4.6 g, 34 mmol) in methylene chloride(250 ml) under nitrogen and cooled over ice/salt to 5° C. (internaltemperature) was added trifluoroacetic acid (82 g, 0.72 mol). Nosignificant temperature rise was noted during the addition. To this wasthen added dropwise a solution of 2,4,6-trimethoxybenzyl alcohol (Munsonet al, J. Org. Chem., 57:3013 (1992)) (6.45 g, 32 mmol) in methylenechloride (150 ml) such that the reaction temperature does not rise above5° C. After the addition was complete, the mixture was stirred for anadditional 5 minutes at 5° C. and the volatiles were removed in vacuo(toluene or ethyl acetate can be used to assist in the removal ofvolatile material). The residue was partitioned between diethyl etherand water and the organic phase dried over anhydrous sodium sulfate,filtered and the volatile material removed in vacuo. The residue wastreated with activated charcoal and recrystalized from diethylether/hexane. The product was isolated as a white solid in 70% yield (7g); mp 103-105° C. ¹H NMR (CDCl₃) δ 6.12 (s, 2H), 3.80-3.85 (m, 11H),2.74 (s, 2H), 1.47 (s, 6H). ¹³C NMR (CDCl₃) δ 173.9, 160.6, 158.6,105.6, 90.5, 55.7, 55.3, 45.9, 43.6, 28.4, 21.0.

[0418] 1b.2,6-bis(diethyl-3-methyl-3(2,4,6-trimethoxyphenylmethylthio)butyric AcidEster)amino)-4,8-dipiperidinopyrimido-[5,4-d]-pyrimidine

[0419] Under a nitrogen atmosphere, dipyridamole (1.50 g, 2.97 mmol) wasdissolved in anhydrous dimethylformamide (30 ml) and4-dimethylaminopyridine (1.46 g, 11.9 mmol) was added, followed by theproduct of Example 1a (3.64 g, 11.9 mmol) and EDAC (2.28 g, 11.9 mmol).The resulting mixture was stirred 44 hours at 50° C. The solvent wasevaporated in vacuo, and residue was partitioned between methylenechloride and water, washed with brine and dried over anhydrous sodiumsulfate. Volatiles were evaporated and the residue was purified by flashchromatography on silica gel, eluting with hexane/ethyl acetate (2:1) to(1:1) to give the title compound (1.02 g, 23% yield). ¹H NMR (CDCl₃, 300MHz) δ 1.45 (s, 24H), 1.58-1.69 (m, 12H), 2.70 (s, 8H), 3.64-3.88 (m,52H), 4.02-4.06 (m, 8H), 4.25-4.32 (m, 8H), 6.10 (s, 8H).

[0420] 1c. 2,6-bis(diethyl-3-methyl-3-mercaptobutyric AcidEster)amino)-4,8-dipiperidinopyrimido-[5,4-d]-pyrimidine

[0421] The product of Example 1b (1.00 g, 0.63 mmol) was dissolved inmethylene chloride (5.5 ml) and anisole (4.0 ml, 36.9 mmol), phenol(0.400 g, 4.25 mmol), water (4.0 ml) and trifluoracetic acid (16 ml, 208mmol) were added. After 1.5 hours of stirring at room temperature,toluene (5 ml) was added and volatiles were evaporated. The residue waspurified by flash chromatography on silica gel eluting with hexane/ethylacetate (5:1) to (3:1) to give the title compound (0.360 g, 59% yield).¹H NMR (CDCl₃, 300 MHz) δ 1.47 (s, 24H), 1.68-1.72 (m, 12H), 2.29 (s,4H), 2.63 (s, 8H), 3.85-3.92 (m, 8H), 3.97-4.03 (m 8H), 4.28-4.35 (m,8H).

[0422] 1d. 2,6-bis(diethyl(3-methyl-3(nitrosothiol)butyric AcidEster)amino)4,8-dipiperidinopyrimido-[5,4-d]-pyrimidine

[0423] The product of Example 1c (0.353 g, 0.36 mmol) was dissolved inacetic acid (20 ml) and 1 N solution of hydrochloric acid (3.5 ml) wasadded, followed by 1 N sodium nitrite solution (2.2 ml). After 30minutes stirring at room temperature, the reaction mixture waslyophilized, the residue was suspended in methylene chloride and washedwith water, brine, and dried over anhydrous sodium sulfate. The solventwas evaporated in vacuo, and the residue was purified by flashchromatography on silica gel eluting methylene chloride/methanol (12:1)to give the title compound (0.144 g, 37% yield). (CDCl₃, 300 MHz) δ1.52-1.73 (m, 12H), 1.98 (s, 24H), 3.20-3.38 (m, 8H), 3.39-3.92 (m,12H), 3.94-4.35 (m, 12H).

Example 21-(4-{{1,3-benzodioxol-5-methyl)amino)-6-chloro-2-quinazolinyl)-4piperidine-carboxylicethyl-(3-methyl-3(nitrosothiol)butyramide)thioester Hydrochloride

[0424] 2a. 3-Methyl-3(thioacetyl)butyric Acid

[0425] To a solution of 3-mercapto-3-methylbutyric acid (Sweetman et al,J. Med. Chem., 14:868 (1971)) (1.03 g, 7.7 mmol) in pyridine (1.6 ml)was added acetic anhydride (1.57 g, 15.4 mmol) and the reaction mixturewas stirred at room temperature over night. The reaction mixture wasslowly added to a 0° C. solution of 1 N HCl (20 ml) then water (10 ml)was added and the reaction mixture was stirred at room temperature for20 hours. The solution was extracted with diethyl ether and the organicphase was washed with brine and then dried over anhydrous sodiumsulfate. The solvent was evaporated in vacuo, and the residue waspurified by flash chromatography on silica gel eluting with ethylacetate/hexane (1:4) to give the title compound (0.791 g, 58% yield).(CDCl₃, 300 MHz) δ 1.55 (s, 6H), 2.25 (s, 3H), 2.99 (s, 2H).

[0426] 2b. Mercaptoethyl-3-methyl-3(thioacetyl)butyramide

[0427] The product of Example 2a (0.556 g, 3.1 mmol) was dissolved inmethylene chloride (10 ml) containing a catalytic amount ofdimethylforamide (10 μl). Oxalyl chloride (0.556 g, 4.4 mmol) was addedand the reaction mixture was stirred at room temperature for 1 hour. Thevolatile components were then evaporated in vacuo and the residueazeotroped with toluene (2×5 ml). The yellow oil remaining was added toa −78° C. solution of 2-aminoethanethiol hydrochloride (0.341 g, 3.0mmol), and triethylamine (0.303 g, 3.0 mmol) in dimethylformamide (6ml). The reaction mixture was stirred at −78° C. for 1 hour and then atroom temperature for 2 hours. The reaction was quenched with water (20ml) and then extracted with ethyl acetate. The organic phase was driedover anhydrous sodium sulfate and then concentrated in vacuo to affordthe title compound (0.349 g, 53% yield) which was used without furtherpurification. (CDCl₃, 300 MHz) δ 1.5 (s, 6H), 2.3 (s, 3H), 2.6 (dd, 2H),2.8 (s, 2H), 2.9 (s, 1H), 3.4 (dd, 2H), 6.0 (brs, 1H).

[0428] 2c. Mercaptoethyl-3-methyl-3(mercapto)butyramide

[0429] The product of Example 2b (0.314 g, 1.4 mmol) was dissolved inmethanol (10 ml) and solid sodium hydroxide (85 mg, 2.1 mmol) was added.After stirring 5 minutes, the reaction mixture was diluted with ethylacetate (50 ml) and washed with saturated aqueous sodium bicarbonate,followed by brine, and then dried over anhydrous sodium sulfate. Thevolatile components were evaporated in vacuo leaving the title compoundas a colorless oil (0.188 g, 75% yield) which was used without furtherpurification. (CDCl₃, 300 MHz) δ: 1.42 (s, 6H), 1.55 (s, 1H), 2.17 (s,1H), 2.41 (s, 2H), 2.61 (dd, J=12.5 Hz, k 6.2 Hz, 2H), 3.39 (dd, J=12.5Hz, 6.2 Hz, 2H).

[0430] 2d. 4-((1,3-benzodioxol-5-ylmethyl)amino)-2,6-dichloroQuinazoline

[0431] A solution of 2,4,6-trichloroquinazoline (0.186 g, 0.80 mmol) inethanol (20 ml) was heated to 55° C. and piperonylamine (0.145 g, 0.96mmol) was added. The resulting mixture was stirred at 55° C. over night.Volatiles were evaporated and the residue was partitioned betweenmethylene chloride and saturated solution of ammonium hydroxide. Theorganic phase was dried over anhydrous sodium sulfate and concentratedin vacuo to yield 0.268 g (96% yield) of the title compound as a whitesolid. ¹H NMR (300 MHz, DMSO) δ 4.59-4.63 (d, 2H), 5.98 (s, 2H), 6.86(s, 2H), 6.96 (s, 1H), 7.62-7.66 (d, 1H), 7.79-7.84 (d, 1H), 8.46 (s,1H), 9.24-9.28 (t, 1H).

[0432] 2e.1-(4-((1,3-benzodioxol-5-ylmethyl)amino)-6-chloro-2-quinazolinyl)-4-piperidine-carboxylicAcid Ethyl Ester

[0433] The product of Example 2d (0.164 g, 0.47 mmol) and ethylisonipecotate (0.200 ml, 1.27 mmol) were combined in 5 g of phenol. Theresulting mixture was heated at reflux temperature (240° C.) for 5hours. The mixture was allowed to cool down, dissolved in 20 mlchloroform and washed with 1 N solution of sodium hydroxide (2×40 ml).The organic fraction was dried over anhydrous sodium sulfate andconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel, eluting with hexane/ethyl acetate (9:1) to (5:1) to give0.164 g (53% yield) of the title compound as a solid. ¹H NMR (300 MHz,CDCl₃) δ 1.24-1.30 (t, 3H), 1.70-1.79 (m, 2H), 1.96-2.06 (m, 2H),2.54-2.58 (m, 1H), 3.01-3.10 (t, 2H), 4.10-4.20 (q, 2H), 4.66-4.70 (d,2H), 4.77-4.84 (d, 2H), 5.59 (s, 1H), 5.97 (s, 2H), 6.77-6.89 (m, 3H),7.40-7.45 (m, 3H).

[0434] 2f.1-(4-((1,3-benzodioxol-5-ylmethyl)amino)-6-chloro-2-quinazolinyl)-4-piperidine-carboxylicAcid

[0435] The product of Example 2e (0.100 g, 0.21 mmol) was dissolved inethanol (1 ml) and water (0.5 ml) was added, followed by sodiumhydroxide (0.082 g, 2.05 mmol). The resulting mixture was heated at 100°C. for 20 minutes. The volatiles were evaporated, the residue wasdiluted with water (2 ml) and 1 N HCl was added until the pH of thereaction mixture registered pH 7. The reaction mixture was then filteredand the precipitate was washed with water (2 ml). Ethanol was added tothe precipitate and the volatiles were evaporated to give 0.080 g (86%yield) of the title compound as a pale yellow solid. ¹H NMR (300 MHz,DMSO) δ 1.36-1.45 (m, 2H), 1.75-1.83 (m, 2H), 2.92-3.02 (m, 3H),4.54-4.60 (m, 4H), 5.94 (s, 2H), 6.83 (s, 2H), 6.93 (s, 1H), 7.21-7.26(d, 1H), 7.44-7.49 (d, 1H), 8.13 (s, 1H), 8.51-8.53 (t, 1H).

[0436] 2g.1-(4-((1,3-benzodioxol-5-ylmethyl)amino)-6-chloro-2-quinazolinyl)-4-piperidine-carboxylicEthyl-(3-methyl-3-(thioacetyl)butyramide)thioester

[0437] Under a nitrogen atmosphere, the product of Example 2f (0.147 g,0.31 mmol) and triethylamine (0.043 ml, 0.31 mmol) were combined in 3 mlof DMF and heated to 50° C. to dissolve all solid. A solution of Example2c (0.067 g, 0.38 mmol) in DMF (2 ml) was added, followed by EDAC (0.073g, 0.38 mmol) and DMAP (0.015 g, 0.12 mmol). The resulting mixture wasstirred at room temperature for 5 hours and then at 50° C. overnight.The reaction mixture was diluted with water (20 ml) and extracted withdichloromethane. The combined organic phase was washed with brine anddried over anhydrous sodium sulfate. The volatiles were evaporated andthe residue was purified by flash chromatography on silica gel elutingwith hexane/ethyl acetate (1:2) to give 0.038 g (21% yield) of the titlecompound. ¹H NMR (300 MHz, CDCl₃) δ: 1.48 (s, 6H), 1.64-1.75 (m, 2H),1.94-2.00 (m, 2H), 2.04 (s, 1H), 2.45 (s, 2H), 2.70-2.77 (m, 1H),2.91-2.96 (t, 2H), 3.01-3.08 (t, 2H), 3.42-3.48 (t, 2H), 4.64-4.68 (d,2H), 4.87-4.94 (d, 2H), 5.64-5.68 (m, 1H), 5.96 (s, 2H), 6.17-6.20 (m,1H), 6.75-6.85 (m, 3H), 7.38-7.45 (m, 3H).

[0438] 2h.1-(4-{{1,3-benzodioxol-5-methyl)amino)-6-chloro-2-quinazolinyl)-4-piperidine-carboxylicEthyl-(3-methyl-3(nitrosothiol)butyramide)thioester Hydrochloride

[0439] The product of Example 2g (0.034 g, 0.057 mmol) was dissolved inmethanol/dichloromethane (1 ml, 1:1) and 4 N HCl in ether (0.100 ml) wasadded. Concentration in vacuo afforded a white solid. The white solidwas then dissolved in a mixture of methylene chloride (3 ml) andmethanol (1 ml), and the resulting solution was cooled to 0° C.Tert-butyl nitrite (0.034 ml, 0.29 mmol) was added and the reactionmixture was stirred at 0° C. for 30 minutes. The volatiles wereevaporated to give 0.037 g (98% yield) of the title compound as a greensolid. ¹H NMR (300 MHz, CDCl₃) δ: 1.61-1.76 (m, 4H), 1.99 (s, 6H),2.66-2.85 (m, 1H), 2.90-3.04 (m, 2H), 3.18-3.45 (m, 4H), 3.48 (s, 2H),4.59-4.86 (m, 4H), 5.87 (s, 2H), 6.62-6.71 (d, 1H), 6.74 (s, 1H),6.80-6.88 (d, 1H), 6.90 (s, 1H), 7.48-7.56 (m, 1H), 7.65-7.76 (m, 1H),8.14-8.19 (d, 1H), 8.43 (s, 1H).

Example 3 In Vitro Comparative Relaxation Responses

[0440] Human corpus cavernosum tissue biopsies were obtained at the timeof penile prosthesis implantation from impotent men. The tissue wasmaintained in a chilled Krebs-bicarbonate solution prior to assay. Thetissue was cut into strips of 0.3×0.3×1 cm and suspended in organchambers for isometric tension measurement. Tissues were incrementallystretched until optimal isometric tension for contraction was obtained.Once this was achieved, the tissues were contracted with phenylephrine(7×10⁻⁷ M) and once a stable contraction was achieved, the tissues wereexposed to either dipyridamole or the compound of Example 1 (10⁻⁶ to3×10⁻⁵ M) by cumulative additions to the chamber. At the end of theexperiment, papaverine (10⁻⁴ M) was added to obtain maximal relaxation.FIG. 58 shows that the compound of Example 1 at doses of 10 μM and 30 μMwas more efficacious in relaxing the phenylephrine-induced contractionthan was an equimolar dose of the phosphodiesterase inhibitordipyridamole. Data were expressed as the percent loss in tone from thephenylephrine-induced contraction (0%=phenylephrine contraction;−100%=tone after administration of papaverine).

Example 4 In Vivo Comparative Erectile Responses

[0441] White New Zealand male rabbits (2.6-3.0 kg) were anesthetizedwith pentobarbital sodium (30 mg/kg). The femoral artery was exposed andindwelled with PE 50 tubing connected to a transducer for recordingsystemic arterial blood pressure. The ventral aspect of the penis wasthen exposed via surgical cut and intracavernosal blood pressure wasmeasured using a 23-gauge needle inserted to the corpus cavernosum. Thecontralateral corpus cavernosum was implanted with a 23-gauge needle forthe administration of drugs.

[0442] Following all surgical procedures, rabbits were allowed to restfor 10 minutes during which intracavernosal blood pressure (ICP) andmean arterial blood pressure (MABP) were continuously recorded. All drugtreatments were administered after stable intracavernosal and systemicblood pressures were established. If an increase in intracavernosalblood pressure (ICP) was observed, the effect was monitored throughoutits entire duration. Animals that did not exhibit an increase in ICPreceived an injection of a combination of phentolamine (0.2 mg) andpapaverine (6.0 mg) to confirm the accuracy of needle implantation andto evaluate the erectile responsiveness of the animal. Animals that didnot respond to this combination were disregarded from the analysis.

[0443] Sildenafil hydrochloride was prepared as an aqueous solution(injection volume 1 ml) and administered intravenously into the earvein. S-nitrosoglutathione (SNO-Glu) was prepared as an aqueous solution(200 μg in 200 μL) and injection intracorporally. Following druginjection the tubing was flushed with 100 μL distilled water. Thefollowing parameters were obtained from each experimental recording: (i)Maximum ICP (mm Hg), (ii) Duration (minutes), defined as the time inminutes, that the increase in ICP is greater than the 50% differencebetween baseline and maximum response. Data were analyzed using ANOVAstatistical analysis (p<0.05).

[0444]FIG. 59 shows the peak erectile response in vivo in theanesthetized rabbit following the administration of (i) sildenafilhydrochloride alone (ii) the combination of sildenafil hydrochloride andSNO-Glu (iii) SNO-Glu alone. FIG. 60 shows the duration of the erectileresponse in vivo in the anesthetized rabbit following the administrationof (i) sildenafil hydrochloride alone (ii) the combination of sildenafilhydrochloride and SNO-Glu (iii) SNO-Glu alone. The administration of thecombination of sildenafil and SNO-Glu shows an unexpected and superiorduration that is greater than the additive effect of sildenafil andSNO-Glu individually.

[0445] Each of the publications, patents and patent applicationsdescribed herein is hereby incorporated by reference herein in theirentirety.

[0446] Various modifications of the invention, in addition to thosedescribed herein, will be apparent to one skilled in the art from theforegoing description. Such modifications are also intended to fallwithin the scope of the appended claims.

What is claimed is:
 1. A method for treating erectile dysfunction in amale individual comprising administering to the individual an effectiveamount of a pharmaceutical composition comprising a Type Vphosphodiesterase inhibitor and L-arginine.
 2. The method of claim 1,wherein the Type V phosphodiesterase inhibitor is zaprinast.
 3. Themethod of claim 1, wherein the Type V phosphodiesterase inhibitor issildenafil.
 4. The method of claim 1, wherein the Type Vphosphodiesterase inhibitor is dipyridamole.
 5. The method of claim 1,further comprising administering to the individual a beta blocker. 6.The method of claim 1, wherein the individual is given a daily dose ofphosphodiesterase inhibitor in the range of approximately 0.001 to 100mg/day.
 7. The method of claim 1, wherein the erectile dysfunction isvasculogenic impotence.
 8. The method of claim 1, wherein thephosphodiesterase inhibitor is contained within a unit dosagepharmaceutical formulation.
 9. A method of inducing vasodilation orinhibiting vasospasm of a coronary artery or bypass graft comprisingcontacting the coronary artery or bypass graft with L-arginine and atype V phosphodiesterase inhibitor, wherein said L-arginine and saidtype V phosphodiesterase the inhibitor act synergistically to induce orincrease vasodilation or to inhibit vasospasm of coronary artery orbypass graft.
 10. The method of claim 9, wherein said L-arginine andsaid phosphodiestersase inhibitor are combined in a single formulation.11. The method of claim 9, wherein the L-arginine and thephosphodiestersase inhibitor are combined with a pharmaceuticallyacceptable carrier.
 12. The method of claim 6, wherein thephosphodiestersase inhibitor is selected from the group consisting ofzaprinast and sildenafil.
 12. The method of claim 9, wherein saidcontacting comprises an intravenous injection of the L-arginine and thephosphodiesterase inhibitor.
 13. The method of claim 9, wherein saidcontacting comprises an oral administration of the L-arginine and thephosphodiesterase inhibitor.
 14. A pharmaceutical composition forinducing vasodilation or inhibiting vasospasm of a coronary artery orbypass graft, said composition comprising L-arginine and a type Vphosphodiesterase inhibitor.
 15. The composition of claim 14, furthercomprising a pharmaceutically acceptable carrier.
 16. The composition ofclaim 14, wherein said type V phosphodiesterase inhibitor is selectedfrom the group consisting of sildenafil and zaprinast.
 17. In a mammal,a coronary artery or bypass graft contacted with an exogenously suppliedL-arginine and an exogenously supplied phosphodiesterase inhibitorwhereby said L-arginine and said phosphodiesterase inhibitor actsynergistically to induce vasodilation or reducing vasospasm of saidcoronary artery or bypass graft.
 18. In the mammal of claim 17, whereinsaid type V phosphodiesterase inhibitor is selected from the groupconsisting of sildenafil and zaprinast.
 19. In the mammal of claim 17,wherein said mammal is a non-human mammal.
 20. A kit for inducingvasodilation or inhibiting vasospasm of a coronary artery or bypassgraft, said kit comprising one or more containers containing:L-arginine; and a type V phosphodiesterase inhibitor.
 21. The kit ofclaim 20, further comprising a pharmaceutically acceptable carrier. 22.The kit of claim 20, wherein said type V phosphodiesterase inhibitor isselected from the group consisting of sildenafil and zaprinast.
 23. Akit for treating erectile dysfunction, said kit comprising one or morecontainers containing: L-arginine; a type V phosphodiesterase inhibitor;and a beta blocker.
 24. A method for treating a sexual dysfunction in apatient in need thereof comprising administering to the patient atherapeutically effective amount of at least one phosphodiesteraseinhibitor and a therapeutically effective amount of at least onecompound that stimulates endogenous nitric oxide, elevates levels ofendogenous endothelium-derived relaxing factor or is a substrate fornitric oxide synthase.
 25. The method of claim 24, wherein the at leastone phosphodiesterase inhibitor is selected from the group consisting ofsildenafil, zaprinast, dipyridamole, filaminast, piclamilast, rolipram,Org 20241, MCI-154, roflumilast, toborinone, vesnarinone, posicar,6-bromo-1,5-dihydro-imidazo(2,1-b)quinazolin-2(3H)-one, R 79595,lixazinone, ICI 153,110, 4,5-dihydro-5-methyl-6-(4-(4-oxo-1(4H)-pyridinyl)phenyl)-3(2H)-pyridazinone, pyrazolopyrimidinones,motapizone, pimobendan, zardaverine, siguazodan, CI 930, EMD 53998,imazodan, saterinone, loprinone hydrochloride, WIN 63291, a3-pyridinecarbonitrile derivative, denbufyllene, albifylline,torbafylline, doxofylline, theophylline, pentoxofylline,4-((1,2-dihydro-2-oxo-6-quinolinyl)oxy)-N-ethyl-N-phenyl-butanamide,nanterinone, cilostazol, cilostamide, MS 857, WIN 62582, bentafentrine,piroximone, milrinone, amrinone, tolafentrine, dipyridamole,papaveroline, E4021, triflusal, a thienopyrimidine derivative, ICOS-351,a tetrahydropiperazino[1,2-b]beta-carboline-1,4-dione derivative, acarboline derivative, a 2-pyrazolin-5-one derivative, a fused pyridazinederivative, a quinazoline derivative, an anthranilic acid derivative, animidazoquinazoline derivative or a pharmaceutically acceptable saltthereof.
 26. The methd of claim 24, wherein the at least onephosphodiesterase inhibitor is a Type V phosphodiesterase inhibitor. 27.The method of claim 26, wherein the Type V phosphodiesterase inhibitoris sildenafil, zaprinast or dipyridamole.
 28. The method of claim 24,wherein the at least one compound that stimulates endogenous nitricoxide, elevates levels of endogenous endothelium-derived relaxing factoror is a substrate for nitric oxide synthase is L-arginine,L-homoarginine, N-hydroxy-L-arginine, nitrosated L-arginine,nitrosylated L-arginine, nitrosated N-hydroxy-L-arginine, nitrosylatedN-hydroxy-L-arginine, citrulline, ornithine, glutamine, or an arginaseinhibitor.
 29. The method of claim 24, wherein the patient is female.30. The method of claim 24, wherein the patient is male.
 31. The methodof claim 24, wherein the compound that stimulates endogenous nitricoxide, elevates levels of endogenous endothelium-derived relaxing factoror is a substrate for nitric oxide synthase and the phosphodiestaseinhibitor are administered orally, by intracavernosal injection, bytransurethral application, or by transdermal application.
 32. The methodof claim 24, wherein the compound that stimulates endogenous nitricoxide, elevates levels of endogenous endothelium-derived relaxing factoror is a substrate for nitric oxide synthase and the phosphodiestaseinhibitor are administered as separate pharmaceutical compositions orare administered together in the form of a single composition.
 33. Themethod of claim 24, further comprising administering to the patient atleast one vasoactive agent.
 34. The method of claim 33, wherein thevasoactive agent is a potassium channel activator, a calcium blocker, anα-blocker, a β-blocker, adenosine, an ergot alkaloid, a vasoactiveintestinal peptide, a dopamine agonist, an opioid antagonist, aprostaglandin, an endothelin antagonist or a mixture of two or morethereof.
 35. A method for treating or preventing a disease induced bythe increased metabolism of cyclic guanosine 3′,5′-monophosphate in apatient in need thereof comprising administering to the patient atherapeutically effective amount of at least one phosphodiesteraseinhibitor and at least one compound that stimulates endogenous nitricoxide, elevates levels of endogenous endothelium-derived relaxing factoror is a substrate for nitric oxide synthase.
 36. The method of claim 35,wherein the disease induced by the increased metabolism of cyclicguanosine 3′,5′-monophosphate is hypertension, pulmonary hypertension,congestive heart failure, renal failure, myocardial infarction, stable,unstable or variant (Prinzmetal) angina, atherosclerosis, cardiac edema,renal insufficiency, nephrotic edema, hepatic edema, stroke, asthma,bronchitis, chronic obstructive pulmonary disease, cystic fibrosis,dementia, immunodeficiency, premature labor, dysmenorrhoea, benignprostatic hyperplasis, bladder outlet obstruction, incontinence, acondition of reduced blood vessel patency, postpercutaneous transluminalcoronary angioplasty, peripheral vascular disease, allergic rhinitis,glucoma, or a disease characterized by a gut motility disorder.
 37. Themethod of claim 35, wherein the disease induced by the increasedmetabolism of cyclic guanosine 3′,5′-monophosphate is a myocardialinfarction; stable, unstable or variant (Prinzmetal) angina; oratherosclerosis.
 38. The method of claim 35, wherein the at least onephosphodiesterase inhibitor is selected from the group consisting ofsildenafil, zaprinast, dipyridamole, filaminast, piclamilast, rolipram,Org 20241, MCI-154, roflumilast, toborinone, vesnarinone, posicar,6-bromo-1,5-dihydro-imidazo(2,1-b)quinazolin-2(3H)-one, R 79595,lixazinone, zaprinast, sildenafil, ICI 153,110,4,5-dihydro-5-methyl-6-(4-(4-oxo-1(4H)-pyridinyl)phenyl)-3(2H)-pyridazinone, pyrazolopyrimidinones,motapizone, pimobendan, zardaverine, siguazodan, CI 930, EMD 53998,imazodan, saterinone, loprinone hydrochloride, WIN 63291, a3-pyridinecarbonitrile derivative, denbufyllene, albifylline,torbafylline, doxofylline, theophylline, pentoxofylline,4-((1,2-dihydro-2-oxo-6-quinolinyl)oxy)-N-ethyl-N-phenyl-butanamide,nanterinone, cilostazol, cilostamide, MS 857, WIN 62582, bentafentrine,piroximone, milrinone, amrinone, tolafentrine, dipyridamole,papaveroline, E4021, triflusal, a thienopyrimidine derivative, ICOS-351,a tetrahydropiperazino[1,2-b]beta-carboline-1,4-dione derivative, acarboline derivative, a 2-pyrazolin-5-one derivative, a fused pyridazinederivative, a quinazoline derivative, an anthranilic acid derivative, animidazoquinazoline derivative or a pharmaceutically acceptable saltthereof.
 39. The methd of claim 35, wherein the at least onephosphodiesterase inhibitor is a Type V phosphodiesterase inhibitor. 40.The method of claim 39, wherein the Type V phosphodiesterase inhibitoris sildenafil, zaprinast or dipyridamole.
 41. The method of claim 35,wherein the compound that stimulates endogenous nitric oxide, elevateslevels of endogenous endothelium-derived relaxing factor or is asubstrate for nitric oxide synthase is L-arginine, L-homoarginine,N-hydroxy-L-arginine, nitrosated L-arginine, nitrosylated L-arginine,nitrosated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine,citrulline, ornithine, glutamine or an arginase inhibitor.
 42. Themethod of claim 41, wherein the compound that stimulates endogenousnitric oxide, elevates levels of endogenous endothelium-derived relaxingfactor or is a substrate for nitric oxide synthase is L-arginine. 43.The method of claim 35, wherein the compound that stimulates endogenousnitric oxide, elevates levels of endogenous endothelium-derived relaxingfactor or is a substrate for nitric oxide synthase and thephosphodiestase inhibitor are administered orally, bucally, parentally,by inhalation, by topical application, or by transdermal application.44. The method of claim 35, wherein the compound that stimulatesendogenous nitric oxide, elevates levels of endogenousendothelium-derived relaxing factor or is a substrate for nitric oxidesynthase and the phosphodiestase inhibitor are administered as separatepharmaceutical compositions or are administered together in the form ofa single composition.
 45. The method of claim 35, further comprisingadministering to the patient at least one vasoactive agent.
 46. Themethod of claim 45, wherein the vasoactive agent is a potassium channelactivator, a calcium blocker, an α-blocker, a β-blocker, adenosine, anergot alkaloid, a vasoactive intestinal peptide, a dopamine agonist, anopioid antagonist, a prostaglandin, an endothelin antagonist or amixture of two or more thereof.
 47. A pharmaceutical compositioncomprising a therapeutically effective amount of at least onephosphodiesterase inhibitor; at least one compound that stimulatesendogenous nitric oxide, elevates levels of endogenousendothelium-derived relaxing factor or is a substrate for nitric oxidesynthase; and at least one pharmaceutically acceptable carrier.
 48. Thepharmaceutical composition of claim 47, wherein the at least onephosphodiesterase inhibitor is a Type V phosphodiesterase inhibitor. 49.The pharmaceutical composition of claim 48, wherein the Type Vphosphodiesterase inhibitor is sildenafil, zaprinast or dipyridamole.50. The pharmaceutical composition of claim 47, wherein the compoundthat stimulates endogenous nitric oxide, elevates levels of endogenousendothelium-derived relaxing factor or is a substrate for nitric oxidesynthase is L-arginine, L-homoarginine, N-hydroxy-L-arginine, nitrosatedL-arginine, nitrosylated L-arginine, nitrosated N-hydroxy-L-arginine,nitrosylated N-hydroxy-L-arginine, citrulline, omithine, glutamine or anarginase inhibitor.
 51. The pharmaceutical composition of claim 47,wherein the compound that stimulates endogenous nitric oxide, elevateslevels of endogenous endothelium-derived relaxing factor or is asubstrate for nitric oxide synthase is L-arginine.
 52. Thepharmaceutical composition of claim 47, wherein the at least onephosphodiesterase inhibitor is selected from the group consisting ofsildenafil, zaprinast, dipyridamole, filaminast, piclamilast, rolipram,Org 20241, MCI-154, roflumilast, toborinone, vesnarinone, posicar,6-bromo-1,5-dihydro-imidazo(2,1-b)quinazolin-2(3H)-one, R 79595,lixazinone, zaprinast, sildenafil, ICI 153,110,4,5-dihydro-5-methyl-6-(4-(4-oxo-1(4H)-pyridinyl)phenyl)-3(2H)-pyridazinone,pyrazolopyrimidinones, motapizone, pimobendan, zardaverine, siguazodan,CI 930, EMD 53998, imazodan, saterinone, loprinone hydrochloride, WIN63291, a 3-pyridinecarbonitrile derivative, denbufyllene, albifylline,torbafylline, doxofylline, theophylline, pentoxofylline,4-((1,2-dihydro-2-oxo-6-quinolinyl)oxy)-N-ethyl-N-phenyl-butanamide,nanterinone, cilostazol, cilostamide, MS 857, WIN 62582, bentafentrine,piroximone, milrinone, amrinone, tolafentrine, dipyridamole,papaveroline, E4021, triflusal, a thienopyrimidine derivative, ICOS-351,a tetrahydropiperazino[1,2-b]beta-carboline-1,4-dione derivative, acarboline derivative, a 2-pyrazolin-5-one derivative, a fused pyridazinederivative, a quinazoline derivative, an anthranilic acid derivative, animidazoquinazoline derivative or a pharmaceutically acceptable saltthereof.
 53. The pharmaceutical composition of claim 47, furthercomprising a therapeutically effective amount of at least one vasoactiveagent.
 54. The pharmaceutical composition of claim 53, wherein thevasoactive agent is a potassium channel activator, a calcium blocker, anα-blocker, a β-blocker, adenosine, an ergot alkaloid, a vasoactiveintestinal peptide, a dopamine agonist, an opioid antagonist, aprostaglandin, an endothelin antagonist or a mixture of two or morethereof.
 55. A pharmaceutical kit comprising a therapeutically effectiveamount of at least one phosphodiesterase inhibitor and a therapeuticallyeffective amount of at least one compound that stimulates endogenousnitric oxide, elevates levels of endogenous endothelium-derived relaxingfactor or is a substrate for nitric oxide synthase.
 56. Thepharmaceutical kit of claim 55, wherein the at least onephosphodiesterase inhibitor is a Type V phosphodiesterase inhibitor. 57.The pharmaceutical kit of claim 56, wherein the Type V phosphodiesteraseinhibitor is sildenafil, zaprinast or dipyridamole.
 58. Thepharmaceutical kit of claim 55, wherein the compound that stimulatesendogenous nitric oxide, elevates levels of endogenousendothelium-derived relaxing factor or is a substrate for nitric oxidesynthase is L-arginine, L-homoarginine, N-hydroxy-L-arginine, nitrosatedL-arginine, nitrosylated L-arginine, nitrosated N-hydroxy-L-arginine,nitrosylated N-hydroxy-L-arginine, citrulline, ornithine, glutamine oran arginase inhibitor.
 59. The pharmaceutical kit of claim 55, whereinthe compound that stimulates endogenous nitric oxide, elevates levels ofendogenous endothelium-derived relaxing factor or is a substrate fornitric oxide synthase is L-arginine.
 60. The pharmaceutical kit of claim55, wherein the at least one phosphodiesterase inhibitor and the atleast one compound that stimulates endogenous nitric oxide, elevateslevels of endogenous endothelium-derived relaxing factor or is asubstrate for nitric oxide synthase are separate components in the kit.61. The pharmaceutical kit of claim 55, wherein the at least onephosphodiesterase inhibitor and the at least one compound thatstimulates endogenous nitric oxide, elevates levels of endogenousendothelium-derived relaxing factor or is a substrate for nitric oxidesynthase are in the form of a single composition in the kit.
 62. Thepharmaceutical kit of claim 55, further comprising a therapeuticallyeffective amount of at least one vasoactive agent.
 63. Thepharmaceutical kit of claim 62, wherein the vasoactive agent is apotassium channel activator, a calcium blocker, an α-blocker, aβ-blocker, adenosine, an ergot alkaloid, a vasoactive intestinalpeptide, a dopamine agonist, an opioid antagonist, a prostaglandin, anendothelin antagonist or a mixture of two or more thereof.